Search

Genetic variation in susceptibility to complex diseases, such as cancer, is well-established. Enrichment of disease associated alleles in specific populations could have implications for disease incidence and prevalence. Prostate cancer (PCa) is a disease with well-established higher incidence, prevalence, and worse outcomes among men of African ancestry in comparison to other populations. PCa is a multi-factorial, complex disease, but the exact mechanisms for its development and progression are unclear. The gene desert located on chromosome 8q24 is associated with aggressiveness of PCa. Interestingly, the non-protein coding gene locus Plasmacytoma Variant Translocation (PVT1) is present at chromosome 8q24 and is overexpressed in PCa. PVT1 gives rise to multiple transcripts with potentially different molecular and cellular functions. In an analysis of the PVT1 locus using data from the 1000 Genomes Project, we found the chromosomal region spanning PVT1 exons 4A and 4B to be highly differentiated between African and non-African populations. We further investigated levels of gene expression of PVT1 exons 4A and 4B and observed significant overexpression of these exons in PCa tissues relative to benign prostatic hyperplasia and to normal prostate tissues obtained from men of African ancestry. These results indicate that PVT1 exons 4A and 4B may have clinical implications in PCa a conclusion supported by the observation that transient and stable overexpression of PVT1 exons 4A and 4B significantly induce greater prostate epithelial cell migration and proliferation. We anticipate that further exploration of the role of PVT1 exons 4A and 4B may lead to the development of diagnostic, therapeutic, and other clinical applications in PCa.

Emerging data indicate that the nervous system plays an important role in carcinogenesis. However, more studies are required to help further elucidate the mechanisms involved in the neural regulation of carcinogenesis. Some recent findings describing the neural regulatory mechanisms of action in prostate cancer, pancreatic cancer and hepatocellular carcinoma are discussed, with a focus on the sympathetic, parasympathetic, and sensory neuronal elements of the nervous system. Norepinephrine, which is released by the sympathetic nervous system and binds to the beta-adrenergic receptor, regulates cellular responses in both normal and tumor cells. It has also been shown that the destruction of sensory neurons can prevent or at least slow pancreatic cancer. Cortisol, the main stress hormone, is also discussed and how it could potentially be involved in hepatocellular carcinoma development. The importance of studying other signaling molecules in the nervous system, such as oxytocin and its receptor, the oxytocin receptor, and how they might be involved in carcinogenesis when aberrantly expressed is highlighted. This is an area of study which clearly needs further investigation. A clearer understanding of the detailed mechanisms of how the nervous system is involved in carcinogenesis could potentially aid in the identification of novel biomarkers and development of novel preventative and therapeutic strategies in various cancers.

PURPOSE: Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related deaths with a very poor prognosis. Consequently, there is an urgent need for better understanding the molecular mechanisms, novel prognostic biomarkers, and more effective treatment options. There is an emerging link between oxytocin (OXT), the oxytocin receptor (OXTR), and cancer. However, the role of OXT or the OXTR in HCC remains unknown. The research question of this study was: Are there genetic alterations in the oxytocin (OXT) and oxytocin receptor (OXTR) genes in hepatocellular carcinoma (HCC) patients and do these alterations impact overall survival and disease-free survival. METHODS: In this retrospective study, we reviewed 360 individual HCC patient data from The Cancer Genome Atlas (TCGA) using cBioPortal accessed in April 2018. The data in The Cancer Genome Atlas are from various institutions in the United States RESULTS: We found that 3% (11 of 360) of cases showed genetic alterations in the OXTR gene. The median months survival was lower for HCC cases with genetic alterations in the OXTR gene as compared to cases without genetic alteration in this gene (33.0 versus 60.84, respectively. Additionally, the median months disease-free survival was lower in cases with genetic alterations in the OXTR gene as compared to cases without alterations (8.64 versus 21.55, respectively). CONCLUSIONS: OXTR is a promising prognostic biomarker for HCC, and OXTR antagonists could have a future role as therapeutic agents for a subset of HCC patients. Further study of the detailed molecular mechanisms of OXT and OXTR in HCC is warranted.

Foreign-born African immigrants bear a large burden of hepatitis B virus (HBV)-related liver disease in the U.S. However, HBV awareness and knowledge of HBV screening and vaccination among this population is limited. This study aimed to provide a better understanding of HBV burden in this vulnerable population and to identify risk factors for the implementation of more effective prevention and treatment programs. We conducted a cross-sectional survey among 71 first-generation African Americans in New York City. Participants’ sociodemographic characteristics, HBV screening and vaccination history, knowledge of HBV transmission, and other related issues were asked. The study sample included 46 men and 23 women, with an average age of 32.75. Of the sample, 87.50% participants migrated from sub-Saharan Africa and 79.10% had lived in the U.S. for 10 or fewer years. Almost half of participants never underwent HBV screening (44.29%) or HBV vaccination (49.23%). About two-thirds (60.87%) of participants never received any HBV screening or vaccination recommendation from doctors. Multivariable analysis results showed that having a college degree and being currently married were significantly associated with HBV screening, while having health insurance was significantly associated with HBV vaccination. Survey data further indicated that first-generation African immigrants had very limited knowledge of HBV transmission, suggesting that this population would benefit from greater awareness of HBV risk factors and modes of transmission. The influence of education, marriage and spousal support, and access to health insurance on HBV screening and vaccination should be noted and further examined in future public health interventions and research.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.

Prostate cancer (PCa) is the most commonly diagnosed solid organ cancer in men worldwide. Current diagnosis of PCa includes use of initial prostate specific antigen assay which has a high false positive rate, low specificity, and low sensitivity. The side effects of unnecessary prostate biopsies that healthy men are subjected to, often result in unintended health complications. New PCa biomarkers are being discovered to address this unmet need. Here, we report on the creation of a composite score (Prostac) based on three recently discovered PCa biomarkers, Plasmacytoma Variant Translocation 1 (PVT1) exons 4A, 4B, and 9. Statistical analysis of copy numbers derived from a real-time quantitative polymerase chain (qPCR) reaction - based assay, showed these PCa biomarkers to be linearly separable and significantly over expressed in PCa epithelial cells. We train a supervised learning algorithm using support vector machines to generate a classification hyperplane from which a user-friendly composite score is developed. Cross validation of Prostac using data from prostate epithelial cells (RWPE1) and PCa cells (MDA PCa 2b) accurately classified 100% of PCa cells. Creation of the Prostac score lays the groundwork for clinical trial of its use in PCa diagnosis.

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (CRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). The 8q24 chromosomal locus is a region of very high PCa susceptibility that carries genetic variants associated with high risk of PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes a cluster of microRNAs including, microRNA-1205 (miR-1205), which are largely understudied. Herein, we demonstrate that miR-1205 is underexpressed in PCa cells and tissues and suppresses CRPC tumors in vivo. To characterize the molecular pathway, we identified and validated fry-like (FRYL) as a direct molecular target of miR-1205 and observed its overexpression in PCa cells and tissues. FRYL is predicted to regulate dendritic branching, which led to the investigation of FRYL in neuroendocrine PCa (NEPC). Resistance toward ADT leads to the progression of treatment related NEPC often characterized by PCa neuroendocrine differentiation (NED), however, this mechanism is poorly understood. Underexpression of miR-1205 is observed when NED is induced in vitro and inhibition of miR-1205 leads to increased expression of NED markers. However, while FRYL is overexpressed during NED, FRYL knockdown did not reduce NED, therefore revealing that miR-1205 induces NED independently of FRYL.

BACKGROUND: Breast lymphomas are rare extranodal lymphomas. They constitute a tiny percentage of malignant tumors of the breast and a small subset of extranodal lymphomas. The rarity of breast lymphomas is attributed to the very scanty lymphoid tissue content of the chest wall. AIMS OF STUDY: This case report aims to provide an up-to-date review of the literature on breast lymphomas and clinicians to consider the possibility of this disease entity while treating a breast mass. CASE PRESENTATION: A case is reported of primary mammary non-Hodgkin lymphoma in a 52-year-old man. Fine needle aspiration cytology (FNAC) was inconclusive. Incisional biopsy-confirmed primary breast lymphoma was diagnosed as the diffuse large B-cell type: non – Hodgkin lymphoma. He had complete disease remission in response to chemotherapy – Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone (CHOP). After that, the patient did not require further surgical intervention. He was followed up at two-monthly intervals for eighteen months in the surgical outpatient clinic with no disease recurrence and satisfactory clinical outcome, following which he discontinued follow-up visits. CONCLUSION: While assessing breast masses, clinicians must recognize primary non-Hodgkin lymphoma as a potential differential diagnosis. A core biopsy of breast masses is needed to exclude it, and appropriate treatment must be given if diagnosed.

The neuropeptide hormone oxytocin, which is released from the posterior pituitary gland, is involved in a number of physiological processes. Understanding of its effects is gradually increasing due to new research in this area. While mostly recognized as a reproductive system hormone, oxytocin also regulates other organ systems such as the brain and cardiovascular system. Recently, research has focused on unraveling its involvement in cancer, and emerging evidence suggests a potential role for oxytocin as a cancer biomarker. This review summarizes observations linking oxytocin and cancer, with a special emphasis on prostate cancer, where it may promote cell proliferation. Research suggests that oxytocin effects may depend on cell type, concentration of the hormone, its interactions with other hormones in the microenvironment, and the precise localization of its receptor on the cell membrane. Future research is needed to further elucidate the involvement of oxytocin in cancer, and whether it could be a clinical cancer biomarker or therapeutic target.

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (mCRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). Resistance to second generation ADTs leads to the progression to AR-independent treatment related-neuroendocrine PCa (t-NEPC), which is observed in nearly 1 in 5 men with mCRPC and is associated with very poor outcomes. PCa neuroendocrine differentiation (PCND) occurs in t-NEPC that is characterized by amplification of Aurora A kinase (AurA). However, the mechanisms that drive t-NEPC are poorly understood. Further understanding PCND in ADT resistance may prevent poorer outcomes. The 8q24 chromosomal locus is an important PCa susceptibility region containing genetic variants associated with increased PCa incidence and aggressiveness. PVT1 is a gene located within this region that encodes microRNA-1205 (miR-1205), whose function is largely unknown. We previously reported miR-1205 underexpression in a cohort of histologically confirmed PCa tissue when compared to normal tissue and that exogenous miR-1205 significantly inhibited tumor growth in CRPC in vivo, suggesting that miR-1205 is a tumor suppressor. To understand the molecular mechanism of miR-1205, we first identfied Fry-like (FRYL) as a direct molecular target of miR-1205. FRYL is predicted to regulate dendritic branching which led us to hypothesize that it is involved in PCND. A Weill Cornell Medicine cohort of 29 benign prostate, 66 localized PCa, 73 CRPC, and 36 NEPC samples whose transcriptome was profiled by RNA-seq, we observed significant overexpression of FRYL in NEPC when compared to localized PCa and benign prostate. After validating FRYL as a target, we examined miR-1205 regulation of FRYL in PCND by culturing LNCaP androgen sensitive PCa cells under androgen deprivation conditions. We observed FRYL mRNA overexpression and significant underexpression of miR-1205 in LNCaP-PCND cells when compared to undifferentiated LNCaP cells. To further characterize this mechanism, miR-1205 was inhibited in RWPE-1 non-tumorigenic and LNCaP cells. As a result, FRYL and AurA protein expression was increased along with NEPC marker expression (Neuron specific enolase 2) when compared to cells transfected with a negative control, suggesting that miR-1205 targets FRYL and AurA to promote PCND. However, RNA pulldown analysis showed that AurA is not a direct target of miR-1205. We observed that FRYL and AurA interaction occurs in LNCaP but not in RWPE-1 cells via co-immunoprecipitation. Interestingly, transfection with miR-1205 mimic inhibits FRYL expression, but not AurA in LNCaP. However, miR-1205 mimic inhibits AurA binding to FRYL. Altogether, these data show that miR-1205 modulates FRYL:AurA protein interaction suggesting that miR-1205 regulation of FRYL:AurA interactions may be important in PCND and t-NEPC. Citation Format: Michelle K. Naidoo, Fayola Levine, Princesca Dorsaint, Andrea Sboner, Olorunseun Ogunwobi. MicroRNA-1205 modulates FRYL/Aurora A kinase protein-protein interaction in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2363.

Summary: Prostate cancer (PCa) is the most commonly diagnosed solid organ cancer in men worldwide. Current diagnosis of PCa includes use of initial prostate specific antigen assay which has a high false positive rate, low specificity, and low sensitivity. Consequently, it results in overdiagnosis and overtreatment, leaving patients with unintended health complications from the side effects of unnecessary prostate biopsies and treatment. PCa biomarkers are being discovered to address this unmet need. Here, we report creation of a composite score based on three PCa biomarkers, plasmacytoma variant translocation 1 exon 4A, exon 4B, and exon 9. Statistical analysis of copy numbers derived from a real-time quantitative polymerase chain reaction - based assay showed these PCa biomarkers to be linearly separable. We trained a supervised learning algorithm using support vector classifiers to generate a classification hyperplane from which a composite score is developed. Our aggregate score when applied to test data from non-cancerous prostate epithelial cells and PCa cells accurately classified 100% PCa cells. Creation of this 3-biomarker based composite score lays the groundwork for clinical trial of its use in PCa diagnosis. Citation Format: Gargi Pal, Emmanuel Asante-Asamani, Leslie Liu, Olorunseun O. Ogunwobi. Computation of a user-friendly composite score from three prostate cancer biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2391.

Triple negative breast cancer (TNBC) is a lethal molecular subtype of invasive breast cancer (BC) that is ER-, PR- and HER2-. Claudin low (CL) TNBC, a distinct molecular subtype of TNBC, has the worst prognosis compared to other BC subtypes. Aberrant expression of claudin proteins disrupts the function of tight junctions. Consequently, inducing epithelial-to-mesenchymal transition (EMT) in cancers, an important factor for enhanced motility and metastasis. Therefore, understanding the molecular mechanisms that modulate claudin expression in TNBC is crucial. The 8q24 genomic locus is an important cancer susceptibility locus that is associated with poor clinical outcomes in cancer due to common amplification events that occur in many malignant diseases. This locus contains the PVT1 gene, which encodes a long noncoding RNA (lncRNA) that has been implicated in multiple cancers including BC. PVT1 consists of 12 exons that are alternatively spliced to generate lncRNAs. Although previous research has implicated PVT1 as an important player in BC, the underlying molecular mechanisms of PVT1 in CL TNBC is unknown. To examine the role of PVT1 in CL TNBC, we assessed PVT1 expression in T47D (ER+), MDA MB 231 (CL) and MDA MB 468 (claudin high (CH)) BC cells. We observed that PVT1 exons 4A, 4B, and 9 are significantly overexpressed in CL MDA MB 231 and significantly underexpressed in CH MDA MB 468 in comparison to T47D cells, suggesting a protumorigenic role of PVT1 in CL TNBC. We analyzed the functional consequences of siRNA targeting of PVT1 exon 9 expression in CL TNBC cells. siRNA targeting of PVT1 exon 9 expression in the MDA MB 231 CL TNBC cells led to a significant reduction in migration and the re-expression of claudin 4. To determine the role of PVT1 on EMT, we assessed the expression of EMT markers (vimentin, fibronectin, and E-cadherin) in MDA MB 231 cells. We observed no changes in the expression of EMT markers when PVT1 exon 9 is knocked down. However, our data show that mesenchymal markers are more highly expressed in MDA MB 231 cells in comparison to MDA MB 468 cells. Further, knockdown of PVT1 exon 9 did not induce apoptosis in MDA MB 231 cells as assessed by caspase 3 and caspase 9 expression. Taken together, our data indicate that PVT1 exon 9 regulates claudin expression and migration in CL TNBC, and may have implications for clinical outcomes in TNBC. Citation Format: Fayola A. Levine, Olorunseun O. Ogunwobi. Targeting PVT1 exon 9 transcript is not pro-apoptotic but induces claudin 4 expression and inhibits migration in triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2387.

One of six deaths globally is due to cancer. In 2018, prostate cancer (PCa) represented 1.28 million cases worldwide, the second most frequent cancer diagnosis and fifth leading cause of death in men. Currently, the mortality rate of PCa has experienced a steady increase due to the progression of metastatic castration-resistant prostate cancer (mCRPC). As an androgen driven disease, androgen deprivation therapies (ADTs) have been employed for treatment. However, despite ADTs, mCRPC develops by maintaining AR signaling, which can eventually lead to progression of AR-independent neuroendocrine PCa (NEPC). NEPC is observable in 1 in 5 men with mCRPC and associated with poor outcome. Therefore, further understanding the mechanisms of progression to mCRPC and NEPC is required. The 8q24 human chromosomal region associated with Increased PCa incidence and aggressiveness contains the PVT1 (Plasmocytoma Variant Translocation 1) locus. The PVT1 locus encodes six microRNAs, including microRNA-1205 (miR-1205) in PCa. Our laboratory previously confirmed that miR-1205 is underexpressed in PCa tissue in comparison to normal prostatic tissue and in CRPC cells in comparison to non-CRPC cells. To understand the molecular mechanism of miR-1205, we performed RNA pull down and RNA sequencing analysis to identify miR-1205 molecular targets in non-tumorigenic RWPE-1 prostate epithelial cells and PCa cells (MDA PCa 2b (metastatic PCa), PC-3 (NEPC), and C4-2B (CRPC)). We identified one cut homeobox 2 (ONECUT2 or OC2) as a direct molecular target of miR-1205. ONECUT2 is a master regulator of transcriptional factors that drives NEPC by through regulating hypoxia signaling or inducing neuroendocrine markers. ONECUT2 enrichment was approximately 3-fold higher in RWPE-1 (P=0.26), 2-fold in PC-3 (P=0.06), 1-fold in C4-2B (P=0.05) and MDA PCa 2b (P=0.02) cells. The significant binding of miR-1205 to ONECUT-2 in the PC-3 NEPC cell line suggests that miR-1205 regulation of ONECUT2 may be an important molecular mechanism in NEPC. Consequently, further study of miR-1205 and ONECUT2 in NEPC is required. Citation Format: Bachelard Dieujuste, Michelle Naidoo, Olorunseun Ogunwobi. MicroRNA-1205 directly targets ONECUT2 in neuroendocrine prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2364.

Prostate cancer is the second most commonly diagnosed male cancer in the world. The molecular mechanisms underlying its development and progression are still unclear. Here we show analysis of a prostate cancer RNA-sequencing dataset that was originally generated by Ren et al. [3] from the prostate tumor and adjacent normal tissues of 14 patients. The data presented here was analyzed using our RNA-sequencing bioinformatics analysis pipeline implemented on the bioinformatics web platform, Galaxy. The relative expression of fibronectin (FN1) and the androgen receptor (AR) were calculated in fragments per kilobase of transcript per million mapped reads, and represented in FPKM unit. A subanalysis is also shown for data from three patients, that includes the relative expression of FN1 and AR and their fold change. For interpretation and discussion, please refer to the article, "miR-1207-3p regulates the androgen receptor in prostate cancer via FNDC1/fibronectin" [1] by Das et al.

Background One of the most important susceptibility loci for cancer is the 8q24 human chromosomal region. The non-protein coding gene locus plasmacytoma variant translocation 1 (PVT1) is located at 8q24 and is dysregulated in prostate cancer. PVT1 gives rise to multiple transcripts which may have different functions. Here, we describe a real-time quantitative polymerase chain reaction (qPCR)-based assay for copy number-based quantitation of PVT1 exons 4A, 4B, and 9 to enable accurate, reproducible, and quantifiable detection. Methods PVT1 exons 4A, 4B, and 9 were cloned into a plasmid vector to create standards for subsequent creation of linear standard curves representing a broad range of concentrations. PCR was carried out using SYBR-Green signal detection to quantify PVT1 exons 4A, 4B, and 9. The efficacy of this assay was evaluated by using it to detect these transcripts in prostate epithelial and prostate cancer cell lines, normal and cancerous human prostate tissues, human serum, mouse plasma, and urine samples. Results The results indicate that the assay can be used to quantify both low and high copy numbers of PVT1-derived transcripts. This is the first report of a copy number-based quantification assay for non-invasive detection of PVT1 derived transcripts. Conclusions This novel assay holds promise for routine non-invasive testing in diseases where PVT1 is dysregulated.

Increasingly cancer is being viewed as a channelopathy because the passage of ions via ion channels and transporters mediate the regulation of tumor cell survival, death, and motility. As a result, a potential targeted therapy for cancer is to use venom peptides that are selective for ion channels and transporters overexpressed in tumor cells. Here we describe the selectivity and mechanism of action of terebrid snail venom peptide, Tv1, for treating the most common type of liver cancer, hepatocellular carcinoma (HCC). Tv1 inhibited the proliferation of murine HCC cells and significantly reduced tumor size in Tv1-treated syngeneic tumor-bearing mice. Tv1&rsquo, s mechanism of action involves binding to overexpressed transient receptor potential (TRP) channels leading to calcium dependent apoptosis resulting from down-regulation of cyclooxygenase-2 (COX-2). Our findings demonstrate the importance of modulating ion channels and the unique potential of venom peptides as tumor specific ligands in the quest for targeted cancer therapies.

Metastasis is the leading cause of cancer death worldwide. Circulating tumor cells (CTCs) are a critical step in the metastatic cascade and a good tool to study this process. We isolated CTCs from a syngeneic mouse model of hepatocellular carcinoma (HCC) and a human xenograft mouse model of castration-resistant prostate cancer (CRPC). From these models, novel primary tumor and CTC cell lines were established. CTCs exhibited greater migration than primary tumor-derived cells, as well as epithelial-to-mesenchymal transition (EMT), as observed from decreased E-cadherin and increased SLUG and fibronectin expression. Additionally, when fibronectin was knocked down in CTCs, integrin B1 and SLUG were decreased, indicating regulation of these molecules by fibronectin. Investigation of cell surface molecules and secreted cytokines conferring immunomodulatory advantage to CTCs revealed decreased major histocompatibility complex class I (MHCI) expression and decreased endostatin, C-X-C motif chemokine 5 (CXCL5), and proliferin secretion by CTCs. Taken together, these findings indicate that CTCs exhibit distinct characteristics from primary tumor-derived cells. Furthermore, CTCs demonstrate enhanced migration in part through fibronectin regulation of integrin B1 and SLUG. Further study of CTC biology will likely uncover additional important mechanisms of cancer metastasis.

Background Oxytocin (OXT) and its receptor (OXTR) is associated with cancer. The present study was to investigate the correlation between the genetic expression alterations of OXT and OXTR and the outcomes in patients with pancreatic cancer (PC). Methods Information regarding OXT and OXTR genetic alterations and changes in gene expression were retrieved from the Cancer Genome Atlas (TCGA) databases and analyzed using the cBioPortal online tool. We assessed the correlation of overall survival and disease/progression-free months to either OXT or OXTR genetic alterations and changes in gene expression using Kaplan-Meier and Cox regression analyses. Quantitative PCR (qPCR) was conducted to assess the mRNA expression levels of OXT and OXTR in human PC cell lines. Results Five percent of PC cases showed mRNA upregulation in the OXT gene. These PC cases also showed genetic alterations and changes in gene expression of OXTR. The median months of survival and disease-free survival were lower for PC cases with genetic alterations and changes in gene expression in the OXT and OXTR genes as compared to those without such alterations. qPCR data showed that OXT and OXTR mRNA expression were 1-fold and 10-fold higher, respectively in PANC-1 cell lines as compared to L3.6pl cell lines in direct negative correlation with responsiveness to gemcitabine. Conclusions These data suggest that OXT and OXTR may potentially be important in PC progression, chemoresistance, and patient survival, and potentially could have prognostic and therapeutic implications in a subset of PC patients.

A strategy for treating the most common type of liver cancer, hepatocellular carcinoma (HCC) applies a targeted therapy using venom peptides that are selective for ion channels and transporters overexpressed in tumor cells. Here, we report selective anti-HCC properties of Tv1, a venom peptide from the predatory marine terebrid snail,Terebra variegata.Tv1 was appliedin vitroto liver cancer cells and administeredin vivoto allograft tumor mouse models. Tv1 inhibited the proliferation of murine HCC cells via calcium dependent apoptosis resulting from down-regulation of the cyclooxygenase-2 (COX-2) pathway. Additionally, tumor sizes were significantly reduced in Tv1-treated syngeneic tumor-bearing mice. Tv1’s mechanism of action involves binding to specific transient receptor potential (TRP) cation channels that are overexpressed in HCC cell models. Our findings demonstrate the unique potential of venom peptides to function as tumor specific ligands in the quest for targeted cancer therapies.

Introduction Many human breast cancers overexpress the E3 ubiquitin ligase MDM2 and its homolog MDMX. Expression of MDM2 and MDMX occurs in estrogen receptor α-positive (ERα+) breast cancer and triple-negative breast cancer (TNBC). There are p53-independent influences of MDM2 and MDMX, and 80% of TNBC express mutant p53 (mtp53). MDM2 drives TNBC circulating tumor cells (CTCs) in mice, but the context-dependent influences of MDM2 and MDMX on different subtypes of breast cancers expressing mtp53 have not been determined. Methods To assess the context-dependent roles, we carried out MDM2 and MDMX knockdown in orthotopic tumors of TNBC MDA-MB-231 cells expressing mtp53 R280K and MDM2 knockdown in ERα+ T47D cells expressing mtp53 L194F. The corresponding cell proliferation was scored in vitro by growth curves and in vivo by orthotopic tumor volumes. Cell migration was assessed in vitro by wound-healing assays and cell intravasation in vivo by sorting GFP-positive CTCs by flow cytometry. The metastasis gene targets were determined by an RT-PCR array card screen and verified by qRT-PCR and Western blot analysis. Results Knocking down MDMX or MDM2 in MDA-MB-231 cells reduced cell migration and CTC detection, but only MDMX knockdown reduced tumor volumes at early time points. This is the first report of MDMX overexpression in TNBC enhancing the CTC phenotype with correlated upregulation of CXCR4. Experiments were carried out to compare MDM2-knockdown outcomes in nonmetastatic ERα+ T47D cells. The knockdown of MDM2 in ERα+ T47D orthotopic tumors decreased primary tumor volumes, supporting our previous finding that estrogen-activated MDM2 increases cell proliferation. Conclusions This is the first report showing that the expression of MDM2 in ERα+ breast cancer and TNBC can result in different tumor-promoting outcomes. Both MDMX and MDM2 overexpression in TNBC MDA-MB-231 cells enhanced the CTC phenotype. These data indicate that both MDM2 and MDMX can promote TNBC metastasis and that it is important to consider the context-dependent roles of MDM2 family members in different subtypes of breast cancer. Electronic supplementary material The online version of this article (10.1186/s13058-018-1094-8) contains supplementary material, which is available to authorized users.

Prostate cancer (PCa) is frequently diagnosed in men, and dysregulation of microRNAs is characteristic of many cancers. MicroRNA-1207-3p is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of microRNA-1207-3p in PCa is unclear. We discovered that microRNA-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells. Increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of FNDC1, a protein which contains a conserved protein domain of fibronectin (FN1). FNDC1, FN1, and the androgen receptor (AR) are significantly overexpressed in PCa cell lines and human PCa, and positively correlate with aggressive PCa. Prostate tumor FN1 expression in patients that experienced PCa-specific death is significantly higher than in patients that remained alive. Furthermore, FNDC1, FN1 and AR are concomitantly overexpressed in metastatic PCa. Consequently, these studies have revealed a novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in PCa.

MicroRNAs (miRNAs) have been found to be dysregulated in prostate cancer (PCa). In this study, we investigated if miR-1207-3p is capable of distinguishing between indolent and aggressive PCa and if it contributes to explaining the disproportionate aggressiveness of PCa in men of African ancestry (moAA). A total of 404 patients with primary adenocarcinoma of the prostate were recruited between 1988 and 2003 at the Moffitt Cancer Center, Tampa, FL, USA. Patient clinicopathological features and demographic characteristics such as race were identified. RNA samples from 404 postprostatectomy prostate tumor tissue samples were analyzed by real-time quantitative reverse transcription polymerase chain reaction for the mRNA expression of miR-1207-3p. miR-1207-3p expression in PCa that resulted in overall death or PCa-specific death is significantly higher than in PCa cases that did not. The same positive correlation holds true for other clinical characteristics such as biochemical recurrence, Gleason score, clinical stage, and prostate-specific antigen level. Furthermore, miR-1207-3p expression was significantly less in moAA in comparison to Caucasian men. We also evaluated whether miR-1207-3p is associated with clinical outcomes adjusted for age at diagnosis and tumor stage in the modeling. Using competing risk regression, the PCa patients with a high miR-1207-3p expression (≥6 vs 3) had a high risk to develop PCa recurrence (hazard rate = 2.5, P < .001) adjusting for age at diagnosis and tumor stage. In conclusion, miR-1207-3p is a promising novel prognostic biomarker for PCa. Furthermore, miR-1207-3p may also be important in explaining the disproportionate aggressiveness of PCa in moAA.

Breast cancer (BC) is a heterogeneous disease that is classically driven by the estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor 2 (EGFR2/HER2) signaling pathways. Triple negative breast cancer (TNBC), is a lethal subtype of invasive BC tumors that are ER-, PR- and HER2-. A subtype of TNBC is claudin low (CL). Dysregulation of claudin proteins disrupts tight junctions, consequently inducing the epithelial-to-mesenchymal transition (EMT) in cancers. This leads to enhanced motility and metastasis. Patients with CL TNBC have worse prognosis than patients with other BC subtypes. PVT1 is a long noncoding RNA (lncRNA) transcribed from the 8q24 genomic locus that has been implicated in multiple cancers including BC. Amplification of the 8q24 gene locus is a common event in many malignant diseases and is associated with poor clinical outcomes. Although previous research has implicated PVT1 as an important player in BC, the underlying molecular mechanisms of PVT1 in CL TNBC was previously unknown. We assessed PVT1 expression in BC, and we observed that PVT1 exons 4A, 4B, and 9 are significantly upregulated in MDA MB 231 cells (claudin low) and significantly downregulated in MDA MB 468 cells (claudin high), in comparison to T47D (ER+). We have confirmed that claudin expression, specifically claudins 1, 3, 4 and 7, are significantly higher in MDA MB 468 cells and significantly lower in MDA MB 231 cells. Knockdown of PVT1 exon 9 expression in the MDA MB 231 cell line, led to a significant reduction in migration when compared to cells transfected with a control scramble siRNA, indicating that PVT1 exon 9 regulates migration in CL TNBC. Interestingly, we observed that claudin 4 expression, and not claudins 1, 3 and 7, was increased in cells where PVT1 exon 9 was knocked down when compared to the control cells. This indicates that PVT1 exon 9 regulates claudin 4 protein stability in CL TNBC. We also assessed the expression of EMT markers (vimentin, fibronectin, and E-cadherin) in MDA MB 231 cells. We observed no changes in EMT markers when PVT1 exon 9 is knocked down; however, our data suggests that EMT markers are more highly expressed in MDA MB 231 cells in comparison to MDA MB 468 cells. Taken together, our data indicate that PVT1 exon 9 regulates claudin expression and migration in CL TNBC, and may have implications for clinical outcomes in TNBC. Citation Format: Fayola Levine, Olorunseun Ogunwobi. PVT1 exon 9 transcript regulates claudin 4 expression and migration in triple negative breast cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-126.

Background Of all liver cancer cases detected in the United States, approximately 70% are caused by hepatitis B and C virus (HBV and HCV). Asian Americans (AAs) are disproportionally affected by liver cancer, with a mortality rate 60% higher than that of non-Hispanic White. In recent years the incidence rate of liver cancer in New York City has been 35% higher than the national average. Methods In New York City, we collaboratively developed and conducted a liver cancer prevention education with community-based organizations to increase awareness of liver cancer prevention and screening. Assessment data was collected from Asian American community members who participated in our educational workshops. Preliminary findings from 53 participants' knowledge on HBV, HCV, and liver cancer prior to the intervention, will be reported in this presentation. Chi-square and t-test were used to conduct data analysis. Results Almost half of the participants reported hearing about HBV (48.1%) and HCV (60.4%) from their medical team, and even fewer of them ever received HBV (37.7%) and HCV (9.4%) testing. Participants were knowledgeable on HBV/HCV transmission (scored 7.9 out of 10), they lack the knowledge on liver cancer risk factors (scored 1.9 out of 5). Those who were covered with health insurance were more knowledgeable on identifying risk factors of liver cancer than those uncovered (1.94 vs. 1.00, p Citation Format: Wenyue Lu, Kerry Traub, Safa Ibrahim, Elizabeth Yi, Ada Wong, Evelyn Gonzalez, Lin Zhu, Marilyn A. Fraser, Yin Tan, Olorunseun Ogunwobi, Grace X. Ma, Ming-Chin Yeh. Hepatitis B and C screening and knowledge of liver cancer in underserved Chinese American adults in New York City: A community-based assessment [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-054.

Background The overall cancer rate is going down across the U.S., however liver cancer incidence is increasing, especially in Philadelphia. Approximately 70% of liver cancer cases are caused by hepatitis B and C virus (HBV and HCV). Notably, Asian Americans (AAs) are disproportionally affected by liver cancer with mortality rate 60% higher than that of non-Hispanic White. Methods We partnered with community-based organizations (CBOs) using community-based participatory research approach. CBOs were involved in all steps of the project, and co- developed/co-delivered community education to increase awareness of liver cancer prevention and screening in Philadelphia. 152 Asian American community members recruited from collaborating CBOs and participated in the educational workshops. Demographic information and knowledge on HBV, HCV, and liver cancer were collected before and after the education. Statistical analysis of Chi-square and t-test were conducted to measure the education’s effect. Results Less than half of the participants rated their health condition as “good and above” (48.95%). With regard to liver cancer prevention awareness, less than one third of the participants had heard about HBV (31.58%) and HCV (21.05%) from their primary care providers, and even fewer of them ever got HBV (21.71%) and HCV (2.63%) testing. Participants’ knowledge increased significantly from the pre-test to the post-intervention evaluation (7.39 vs. 9.24, p Citation Format: Kerry Traub, Lin Zhu, Wenyue Lu, Safa Ibrahim, Elizabeth Yi, Ada Wong, Evelyn Gonzalez, Marilyn Fraser, Yin Tan, Grace Ma, Olorunseun Ogunwobi, Ming-Chin Yeh. A culturally-sensitive and linguistically competent community-based hepatitis B and C intervention for underserved Asian American communities [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-053.

Women and racial/ethnic minorities are underrepresented in the biomedical, clinical, behavioral, and social sciences. One of the main goals of the Synergistic Partnership for Enhancing Equity in Cancer Health (SPEECH), a comprehensive regional cancer health disparity partnership between Temple University/Fox Chase Cancer Center (TUFCCC) and Hunter College (HC), is to diversify and expand the pool of researchers trained to conduct research on cancer and cancer health disparities. Specifically, the SPEECH partnership’s efforts towards mentorship and training involve several cores that capitalize on numerous strengths in training and research education across TUFCCC, an NIH-designated Comprehensive Cancer Center, and HC, a Minority Serving Institution, to facilitate the professional enrichment of students and junior investigators underrepresented in cancer research. To effectively monitor and evaluate the training activities under the SPEECH partnership, we established a long- term tracking system. The development of the tracking system began by identifying the fields of research training (basic, translational, behavioral/population science), levels of trainees (undergraduate, graduate, early-stage-investigators), and types of training activities (Summer Cancer Research Institute, Mentored Research Projects, Cancer Research Fellows, etc.). Next, was the identification of several outcome measures, including trainee’s interests, preparedness, and professional accomplishments in cancer and cancer health disparities research. To facilitate data collection, we established a web-based, centralized evaluation portal to document trainees’ and mentee information and achievements, as well as research grant submissions and publications within the SPEECH partnership. For long-term tracking of trainee education and career progressions, we intend to maintain contact with previous and on-going trainees through emails and social media. In the interest of comparing the understanding of cancer biology and of health disparities, we intend to conduct a cross-sectional survey of a random sample of SPEECH trainees and a random sample of non-SPEECH trainees with the goal of identifying any differences between the two groups in familiarity with and understanding of cancer biology and of health disparities. We will present the process of developing the long-term tracking system, our achievements, as well as challenges. Citation Format: Lin Zhu, Marsha Zibalese- Crawford, Sarah-Jane Dodd, Carolyn Y. Fang, Yin Tan, Olorunseun O. Ogunwobi, Grace X. Ma. Establishing long-term tracking to evaluate the effectiveness of a partnership-led training program to advance the careers of cancer health disparities trainees from underrepresented groups [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-066.

Background Liver cancer incidence and death rate are on the rise in the US. racial/ethnic populations are disproportionally affected by liver cancer; from 1994 to 2014, liver cancer death rate rose by 57% in black/African Americans and 69% in Hispanic Americans, and Asian Americans’ liver cancer mortality rate is 60% higher than that of non-Hispanic White. About 65% to 70% of liver cancer cases are caused by hepatitis B and C virus (HBV and HCV). Limited studies or programs have focused on addressing liver cancer in multiple disparity racial/ethnic populations. Methods The Community Outreach Core team of NCI funded U54 TUFCCC/HC Partnership engaged ten community-based organizations (CBOs) and jointly initiated a community-based HBV/HCV liver cancer prevention initiative, aimed to increase HBV and HCV screening in African, Asian and Hispanic American Communities using training community peer educators to co-implement the education. 503 community participants living in New York City and Greater Philadelphia areas participated in this initiative, and completed pre-, and post-education tests. Paired t test was used to measure the knowledge change from pre- to post-education, and Chi square test was conducted to detect the HBV/HCV testing among different racial/ethnic groups. A p value lower than 0.05 is considered statistically significant. All data analysis was conducted in Stata 15. Results All participants were from liver cancer disparity populations, including Asian (54.94%), African American (15.10%), and Hispanic (29.95%) Americans. Overall, significantly improved knowledge on HBV/HCV and liver cancer prevention were observed after the education. Participants’ average knowledge score on HBV/HCV increased significantly from pre- to post-education (7.14/10 vs.9.02/10, p Citation Format: Wenyue Lu, Kerry Traub, Safe Ibrahim, Lin Zhu, Evelyn Gonzalez, Ada Wong, Nathaly Rubio-Torio, Grace Ma, Olorunseun Ogunwobi, Marilyn Fraser, Ming-Chin Yeh, Yin Tan. A community-engaged hepatitis B and C screening intervention in medically underserved African, Asian and Hispanic American communities [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-243.

The incidence and mortality rate of prostate cancer (PCa) is highest in males of African ancestry. PCa is a multi-factorial, complex disease, but the exact mechanisms for its development and progression are unclear. Analysis of data from the one thousand genomes project revealed that a 26-kb region spanning PVT1 exons 4A and 4B shows a run of 75 SNPs with distinct allelic frequencies between African and non-African populations. The gene desert located on chromosome 8q24 is associated with aggressiveness of PCa in males of African ancestry. Interestingly, the non-protein coding gene locus Plasmacytoma Variant Translocation (PVT1) present at 8q24 is overexpressed in PCa. PVT1 gives rise to multiple transcripts with potentially different functions. To investigate if our observed population-level differences at the PVT1 gene locus have implications for PCa, we determined the expression of PVT1 exons 4A and 4B in histologically confirmed normal prostate (n=22), benign tumor prostate (n=35), and malignant tumor prostate tissue (n=28) samples obtained from males who had undergone prostatectomy or transrectal ultrasound-guided biopsy in Nigeria, a sub-Saharan Black African population. We have observed that PVT1 exons 4A and 4B are significantly overexpressed in PCa tissues in comparison to others. Transient and stable overexpression of PVT1 exons 4A and 4B significantly induce greater prostate epithelial cell migration and proliferation. We anticipate that further exploration of the role of PVT1 exons 4A and 4B may lead to the possibility of exploiting them for diagnosis, therapy, and other clinical applications in PCa. Citation Format: Gargi Pal, Lia Di, Akintunde Orunmuyi, E. Oluwabunmi Olapade-Olaopa, Weigang Qiu, Olorunseun O. Ogunwobi. Population level genetic differentiation at the PVT1 gene locus: Implications for prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1411.

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (mCRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). Resistance to second generation ADTs leads to the progression to AR-independent neuroendocrine PCa (NEPC), which is observed in nearly 1 in 5 men with mCRPC and is associated with very poor outcome. PCa neuroendocrine differentiation (PCND) is observed in treatment related NEPC, however, this mechanism is poorly understood. Therefore, further understanding of PCND in ADT resistance may prevent poorer outcomes. The 8q24 chromosomal locus is an important prostate cancer (PCa) susceptibility region containing genetic variants associated with increased PCa incidence and aggressiveness. PVT1 is a gene located within this region that encodes microRNA-1205 (miR-1205), whose function is largely unknown. We have previously reported that miR-1205 is underexpressed in a cohort of histologically confirmed PCa tissue obtained from moAA, when compared to normal tissue and is also underexpressed in vitro in CRPC cells, when compared to non-CRPC cells. We also demonstrated that exogenous miR-1205 significantly inhibited tumor volume in CRPC-derived xenograft male NOD/SCID gamma mice, suggesting that miR-1205 is a tumor suppressor. To understand the molecular mechanism of miR-1205, we demonstrated that miR-1205 directly targets Fry-like (FRYL) by performing an RNA pulldown assay. FRYL is predicted to regulate dendritic branching leading to the hypothesis that FRYL plays a role in PCND. To examine miR-1205 regulation of FRYL in PCND in vitro, LNCaP cells were cultured under androgen deprivation conditions for fourteen days. We observed FRYL mRNA overexpresssion and a significant reduction of miR-1205 expression in LNCaP-PCND cells when compared to undifferentiated LNCaP cells. To further determine whether this mechanism drives PCND, miR-1205 was inhibited in RWPE-1 and LNCaP androgen-sensitive cells. As a result, FRYL protein expression was increased along with neuroendocrine marker expression (Neuron specific enolase 2) when compared to cells transfected with a negative control. To determine whether PCND is driven directly through FRYL activity, FRYL was silenced using an siRNA in PC-3 cells (model of NEPC). Interestingly, knockdown of FRYL did not reveal a decrease of neuroendocrine markers, suggesting that miR-1205 may induce PCND independently of FRYL. Further investigation into the role of miR-1205 and FRYL in PCND is required. Further understanding this molecular mechanism may provide novel insights into overcoming ADT resistance in aggressive PCa. Citation Format: Michelle K. Naidoo, Fayola Levine, Xavier Graña, Olorunseun Ogunwobi. MicroRNA-1205 directly binds to FRYL and suppresses aggressive prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2532.

Prostate cancer (PCa) is the most common non-skin cancer and the second leading cause of cancer-related death for men in the United States. PCa is the greatest source of cancer-related mortality in males of African ancestry. One of the most important susceptibility loci for cancer is the 8q24 human chromosomal region. The non-protein coding gene locus plasmacytoma variant translocation 1 (PVT1) is located at 8q24 and is dysregulated in different cancers. PVT1 gives rise to several alternatively spliced transcripts and microRNAs. There are at least twelve exons of PVT1, which make separate transcripts, and likely have different functions. The transcript from PVT1 exon 9 is significantly overexpressed in PCa tissues in comparison to normal prostate tissues obtained from Black males. Both transient and stable overexpression of PVT1 exon 9 induce significantly increased prostate epithelial cell proliferation, migration, and proliferating cell nuclear antigen (PCNA) expression. Notably, implantation into mice of a novel subline of a non-tumorigenic prostate epithelial cell line stably overexpressing PVT1 exon 9 results in the formation of malignant tumors with features characteristic of aggressive PCa. Further, PVT1 exon 9 overexpression significantly induces castration-resistance in prostate epithelial cells. Consequently, PVT1 exon 9 expression is important for PCa initiation and progression and may have potential diagnostic and therapeutic applications in PCa in Black males. Citation Format: Gargi Pal, Jeannette Huaman, Fayola Levine, Akintunde Orunmuyi, E. Oluwabunmi Olapade-Olaopa, Olorunseun O. Ogunwobi. The long noncoding RNA from PVT1 exon 9 is overexpressed in prostate cancer in Black males and induces malignant transformation, invasiveness, and castration-resistance in prostate epithelial cells [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B074.

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (mCRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). Resistance towards second generation ADTs leads to the progression of AR-independent neuroendocrine PCa (NEPC) phenotypes, which are observed in nearly 1 in 5 men with mCRPC and is associated with short survival rates. Moreover, men of African ancestry (moAA) have a higher NEPC incidence and mortality rates, compared to Caucasian males. PCa neuroendocrine differentiation (PCND) is observed in treatment related NEPC, however, this mechanism is poorly understood. Therefore, further understanding of PCND in ADT resistance may prevent poorer outcomes. The 8q24 chromosomal locus is an important PCa susceptibility region containing genetic variants associated with increased PCa incidence among moAA. PVT1 is a gene located within this region that encodes microRNA-1205 (miR-1205), whose function is largely unknown. We have previously reported that miR-1205 is underexpressed in a cohort of histologically confirmed PCa tissue obtained from moAA, when compared to normal tissue and is also underexpressed in vitro in CRPC cells, when compared to non-CRPC cells. We also demonstrated that exogenous miR-1205 significantly inhibited tumor volume in CRPC-derived xenograft male NOD/SCID gamma mice, suggesting that miR-1205 is a tumor suppressor. To understand the molecular mechanism of miR-1205, we demonstrated that miR-1205 directly targets Fry-like (FRYL). FRYL is predicted to regulate dendritic branching leading to the hypothesis that FRYL plays a role in PCND. To examine miR-1205 regulation of FRYL in NEPC, we examined RNA sequencing data from a cohort of histologically confirmed NEPC tissues (n=14) and PCa adenocarcinoma tissues (n=30) obtained from TCGA using the cBioPortal platform. We observed increased FRYL mRNA expression in NEPC tissues when compared to PCa adenocarcinoma tissues. In vitro data revealed that FRYL mRNA was overexpressed and miR-1205 was significantly underexpressed after fourteen days of induced PCND differentiation using LNCaP cells when compared to undifferentiated LNCaP cells. Lastly, we performed RNA pulldown, and subsequent RNA sequencing to identify the molecular targets of miR-1205. Interestingly, we observed that in addition to FRYL, the AURKA gene, which is amplified during PCND, was significantly enriched. In conclusion, these data suggest that miR-1205 regulation of FRYL may be a critical mechanism in NEPC. Further understanding this molecular mechanism may provide novel insights into overcoming ADT resistance in aggressive PCa that disproportionally affects moAA. Citation Format: Michelle K Naidoo, Fayola Levine, Xavier Graña-Amat, Olorunseun Ogunwobi. Molecular mechanisms of microRNA-1205 in aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B090.

Men of African ancestry (moAA) have increased likelihood for development of aggressive prostate cancer (PCa). PCa deaths are often associated with castration-resistant prostate cancer (CRPC) due to maintenance of androgen receptor (AR) signaling in PCa cells following androgen ablation therapy (ADT). The 8q24 chromosomal locus is a highly susceptible PCa region that carries risk genetic variants associated with increased incidence of aggressive PCa in moAA. This region also carries frequent amplifications of the PVT1 gene, a nonprotein coding gene that encodes microRNA-1205 whose function was previously unknown. We examined miR-1205 mRNA expression in a cohort of normal (n=22), benign prostatic hyperplasia (n=42), and PCa (n=26) histologically confirmed prostatic tissues obtained from prostatectomy or transrectal biopsies of moAA in Ibadan, Nigeria. A Tukey post hoc test revealed decreased miR-1205 expression in benign prostatic hyperplasia (4.61 ± 7.5) and PCa (3.39 ± 3.53) when compared to normal tissues (6.55 ± 9.5), suggesting that miR-1205 may function as a tumor suppressor and loss of miR-1205 is characteristic of PCa in moAA. In vitro studies revealed decreased miR-1205 expression in CRPC (C4-2B and 22RV1) cells when compared to non-CRPC (LNCaP) cells, suggesting a role for miR-1205 in CRPC. Furthermore, we observed significant inhibition of tumor growth in NOD/SCID gamma mice implanted with C4-2B cells that were administered our novel synthetic analog of miR-1205 (patent pending) when compared to mice treated with a scramble oligonucleotide, indicating that miR-1205 can suppress CRPC tumors. We identified Fry-like (FRYL) as a putative target of miR-1205 using a miSVR computer algorithm and subsequently observed FRYL and AR overexpression in prostate tumors compared to normal tissue from fourteen PCa patients when whole-transcriptome analysis was performed using the Galaxy web platform. Moreover, FRYL was overexpressed in CRPC cells when compared with non-CRPC cells, further suggesting a role in CRPC development. C4-2B cells transfected with miR-1205 and the 3′ UTR of FRYL in a luciferase expressing vector revealed a significant decrease in luciferase activity when compared to control cells, indicating direct binding of miR-1205 to the 3′ UTR of FRYL. These observations strongly suggest that miR-1205 acts as a tumor suppressor by directly targeting FRYL mRNA in PCa cells. FRYL is predicted to regulate dendritic branching, leading to our hypothesis that FRYL plays a role in the development of PCa with neuroendocrine differentiation (PCND), a resulting mechanism due to ADT resistance. We observed that FRYL mRNA was overexpressed and miR-1205 was significantly underexpressed after fourteen days of inducing PCND in LNCaP cells, suggesting that miR-1205 regulation of FRYL mRNA may play a role in PCND development. Further understanding miR-1205 regulation of FRYL may provide novel insights into the molecular mechanisms of aggressive PCa. This abstract is also being presented as Poster B068. Citation Format: Michelle K. Naidoo, Fayola Levine, Tamara Gillot, Thahmina Ali, Konstantinos Krampis, Akintunde Orunmuyi, E.O. Olapade-Olaopa, Olorunseun O. Ogunwobi. MicroRNA-1205 regulation of FRYL and aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr PR09.

Prostate cancer (PCa) is the second most common cause of cancer-specific deaths in the United States, accounting for approximately 13% of cancer-related deaths. PCa is also the leading cancer in terms of incidence and mortality in men from Africa and the Caribbean. PCa is a multifactorial, complex disease, with the exact mechanisms for its development and progression unclear. Understanding the molecular mechanisms underlying the development and progression of PCa is necessary. This will aid in the discovery of novel and efficacious biomarkers with applications in early PCa detection and molecular therapeutic targeting. The non-protein coding gene locus Plasmacytoma Variant Translocation (PVT1) is located at 8q24 and is overexpressed in PCa. PVT1 has at least 12 exons that make separate transcripts having different functions. We have recently shown that PVT1 exons 4A and 4B are significantly overexpressed in prostate cancer tissues of Black males and are potential clinical biomarkers for prostate cancer in Black males. In this study, the role of PVT1 exons 4A and 4B in the migration and proliferation of prostate epithelial cells was examined. PVT1 exons 4A and 4B gene fragments were cloned into plasmid expression vectors and transfected into the RWPE1 prostate epithelial cell line to examine their effect on prostate epithelial cell proliferation and migration. We observed that overexpression of either PVT1 exon 4A, or PVT1 exon 4B significantly increased prostate epithelial cell migration and proliferation. This indicates that PVT1 exons 4A and 4B are functional biomarkers for prostate cancer. Better understanding of the roles of PVT1 exons 4A and 4B in PCa may lead to the future possibility of exploiting them for diagnosis, therapy, and other clinical applications in PCa. Citation Format: Gargi Pal, Olorunseun Ogunwobi. PVT1 exons 4A and 4B overexpressed in prostate cancer in black males regulate prostate epithelial cell proliferation and migration [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B044.

Background: Liver cancer increased 72 percent between 2003 and 2012 in the US. Similarly, the liver cancer death rates in the US are increasing faster than for any other cancer, having doubled since the mid-1980s. People with hepatitis B and C have the greatest risk of liver cancer. In the US, approximately 65 percent of liver cancer cases are related to hepatitis B or C (HBV or HCV), with nearly 50 percent attributable to hepatitis C alone. Objective: The Community Outreach Core (COC) Program is a part of the NCI funded TUFCCC/HC Regional Cancer Health Partnership Program and targets areas of Pennsylvania, New Jersey, and New York City. One of the most important goals of the COC is engaging community partners in cancer outreach research to reduce cancer disparities among underserved minority populations in the Partnership targeted geographic areas using Community-Based Participatory Research (CBPR) approaches.The purpose of this project is to mobilize the community to increase awareness of hepatitis B and C, and empower community members to talk to their trusted doctors about hepatitis B and C and to be tested. Method: The campaign features an educational advertisement on SEPTA buses (Southeastern Pennsylvania Transportation Authority) in Philadelphia City, PA. The promotional messages included culturally tailored educational messages targeting high risk residents with HBV or HCV related liver disease. The central message of the ad calls for action of “getting screened for HBV and HCV”. The Campaign ad poster (21”x22”) posted in 115 buses traveling in the City of Philadelphia for 4 weeks. In total, 938,280 bus riders had a chance to view the ad information. 173 survey forms were collected from diverse racial/ethnicity bus riders both men and women during the campaign period. Results: Among the 173 respondents, 22.7% of them reported “saw advertisement on the bus.” Specifically, riders who saw the advertisement are significantly more likely to get screened for HBV/HCV than those who did not see the advertisement (86.5% vs 58.3%). Conclusion: The findings of the project suggested that culturally tailored educational messages can effectively promoting HBV/HCV screening. The next steps of community outreach strategies will also be discussed. Citation Format: Kerry L Traub, Jean Marie Kouassi, Evelyn González, Elizabeth Yi, Safa Ibrahim, Wenyue Lu, Yin Tan, Ming-Chin Yeh, Olorunseun O Ogunwobi, Marilyn A Fraser. Reducing liver cancer disparities through culturally tailored educational messages: A city-wide bus campaign in Philadelphia City [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B027.

Colorectal cancer is the second most common cause of cancer deaths in the United States, and it disproportionally affects minority populations. Poor dietary habits, such as diet low in fruits and vegetables, increase the risk of colorectal cancer. Moreover, socioeconomic factors contribute to limited access to fresh and healthy foods and limited opportunities for safe physical activity, leading to poor physical health. In this interdisciplinary study, we aim to investigate any relationships between dietary behaviors and cancer risk in adults aged 50 years and above. We are recruiting participants at a senior center in East Harlem, New York City, a racially diverse and underserved community. The participants complete a NIH-validated survey through which we assess their dietary habits and collect standardized demographic data and history of cancer. Urine samples from participants are analyzed for polyphenols, commonly found in fruits and vegetables. Quantification of polyphenol content in urine is determined by a standard curve based on the concentration of gallic acid, a stable and convenient chemical that is representative of polyphenols from fruits and vegetables. So far, analysis of urine from a cohort of diverse participants (n=15) has been performed. The range of gallic acid concentration obtained was 3.85-17.14 μg/mL. We observed the lowest gallic acid concentration in a participant with history of cancer, suggesting low level of polyphenol content in their urine. Ongoing work includes further recruitment of participants and an intervention consisting of active nutritional education (cooking classes, workshops, etc.). A control group that will not receive this educational intervention will be provided with brochures through mail informing them about general health information. At the end of the intervention period, urine will be collected and analyzed to assess the impact of nutritional education on dietary habits in underserved and minority communities. Citation Format: Cristina N. Zambrano, Maayan Beeber, April Panitz, Yin Tan, Grace Ma, Khursheed Navder, Ming-Chin Yeh, Olorunseun Ogunwobi. Diet and risk of cancer in minority populations in New York City [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C047.

Characterized by poor prognosis, high mortality, and frequent relapse, hepatocellular carcinoma (HCC) is one of the deadliest cancers. People with HCC frequently present with advanced disease. There is a paucity of treatment options for patients once they have reached this stage. Apart from sorafenib, a tyrosine kinase inhibitor which extends survival of HCC patients by only a few months, there is currently no other effective treatment for advanced HCC. Epithelial-to-mesenchymal transition (EMT) plays an important role in HCC development and progression. Consequently, EMT markers may have applications in the diagnosis and treatment of HCC. And data from preclinical and clinical trials suggest that there may be potential for success in harnessing EMT markers for the diagnosis of HCC, and specific targeting of EMT markers may have potential usefulness for the treatment of advanced HCC.

Prostate cancer is the most common malignancy among men in the US. Though considerable improvement in the diagnosis of prostate cancer has been achieved in the past decade, predicting disease outcome remains a major clinical challenge. Recent expression profiling studies in prostate cancer suggest microRNAs (miRNAs) may serve as potential biomarkers for prostate cancer risk and disease progression. miRNAs comprise a large family of about 22-nucleotide-long non-protein coding RNAs, regulate gene expression post-transcriptionally and participate in the regulation of numerous cellular processes. In this review, we discuss the current status of miRNA in studies evaluating the disease progression of prostate cancer. The discussion highlights key findings from previous studies, which reported the role of miRNAs in risk and progression of prostate cancer, providing an understanding of the influence of miRNA on prostate cancer. Our review indicates that somewhat consistent results exist between these studies and reports on several prostate cancer related miRNAs. Present promising candidates are miR-1, -21, 106b, 141, -145, -205, -221, and -375, which are the most frequently studied and seem to be the most promising for diagnosis and prognosis for prostate cancer. Nevertheless, the findings from previous studies suggest miRNAs may play an important role in the risk and progression of prostate cancer as promising biomarkers.

Prostate cancer (PCa) is the second most common cause of cancer-specific deaths in the U.S. Unfortunately, the underlying molecular mechanisms for its development and progression remain unclear. Studies have established that microRNAs (miRNAs) are dysregulated in PCa. The intron-derived microRNA-1207-3p (miR-1207-3p) is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, miR-1207-3p in PCa had not previously been investigated. Therefore, we explored if miR-1207-3p plays any regulatory role in PCa. We discovered that miR-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells, and that increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of fibronectin type III domain containing 1 (FNDC1). Our studies also revealed significant overexpression of FNDC1, fibronectin (FN1) and the androgen receptor (AR) in human PCa cell lines as well as tissues, and FNDC1, FN1, and AR positively correlate with aggressive PCa. These findings, recently published in Experimental Cell Research, are the first to describe a novel miR-1207-3p/FNDC1/FN1/AR novel regulatory pathway in PCa.

Circulating tumor cells (CTCs) from peripheral blood hold important information for cancer diagnosis and disease monitoring. Analysis of this “liquid biopsy” holds the promise to usher in a new era of personalized therapeutic treatments and real-time monitoring for cancer patients. But the extreme rarity of CTCs in blood makes their isolation and characterization technologically challenging. This paper reports the development of a geometrically enhanced mixing (GEM) chip for high-efficiency and high-purity tumor cell capture. We also successfully demonstrated the release and culture of the captured tumor cells, as well as the isolation of CTCs from cancer patients. The high-performance microchip is based on geometrically optimized micromixer structures, which enhance the transverse flow and flow folding, maximizing the interaction between CTCs and antibody-coated surfaces. With the optimized channel geometry and flow rate, the capture efficiency reached >90% with a purity of >84% when capturing spiked tumor cells in buffer. The system was further validated by isolating a wide range of spiked tumor cells (50–50,000) in 1 mL of lysed blood and whole blood. With the combination of trypsinization and high flow rate washing, captured tumor cells were efficiently released. The released cells were viable and able to proliferate, and showed no difference compared with intact cells that were not subjected to the capture and release process. Furthermore, we applied the device for detecting CTCs from metastatic pancreatic cancer patients’ blood; and CTCs were found from 17 out of 18 samples (>94%). We also tested the potential utility of the device in monitoring the response to anti-cancer drug treatment in pancreatic cancer patients, and the CTC numbers correlated with the clinical computed tomograms (CT scans) of tumors. The presented technology shows great promise for accurate CTC enumeration, biological studies of CTCs and cancer metastasis, as well as for cancer diagnosis and treatment monitoring.

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (mCRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). Resistance to second generation ADTs further leads to progression to neuroendocrine PCa (NEPC), which is observed in nearly 1 in 5 men with mCRPC and is associated with low survival rates. The molecular mechanisms of progression to NEPC are, however, still unclear. Further understanding of molecular mechanisms of NEPC is critical to improving patient outcomes. The 8q24 chromosomal locus is a highly susceptible PCa region that carries high risk genetic variants associated with PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes microRNA-1205 (miR-1205). We have previously reported that miR-1205 is underexpressed in PCa tissues in comparison to normal prostate tissue, and is also underexpressed in vitro in CRPC cells in comparison to non-CRPC cells. We also demonstrated that exogenous miR-1205 significantly inhibited tumor volume in CRPC tumor xenografts in mice, and that miR-1205 directly targets the putative oncogene, Fry-like (FRYL). FRYL is predicted to regulate dendritic branching leading to the hypothesis that FRYL plays a role in NEPC. To test this hypothesis, we first examined miR-1205 expression levels in PCa tissues with Gleason scores ≥8 and Citation Format: Michelle K. Naidoo, Olorunseun Ogunwobi. MicroRNA-1205 regulation of FRYL in neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 775.

Sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), but the underlying molecular mechanisms remain controversial and why some patients do not respond to this therapy is poorly understood. In this study, we show that sorafenib triggers cell growth inhibition and apoptosis in HCC cells by directly targeting the mitochondria. Treatment with sorafenib induces rapid mitochondrial fragmentation, which is associated with the deregulation of mitochondria fusion-related protein optic atrophy 1 (OPA1). Exposure of cells or isolated mitochondria to sorafenib substantially induces cytochrome c release. Our data indicate that siRNA-mediated OPA1 knockdown significantly sensitizes HCC cells to sorafenib-induced apoptosis. Furthermore, sorafenib has no apparent apoptotic toxicity to normal human primary hepatocytes. Sorafenib inhibits HCC xenograft tumor growth in vivo and murine xenograft tumor tissue analysis reveals mitochondria fusion protein. OPA1 expression levels are strongly downregulated by sorafenib treatment. Western blotting evaluation of patient HCC with matched non-tumor tissue samples demonstrates that OPA1 expression is decreased in up to 40% of HCC patients. Taken together, we have shown that sorafenib suppresses the tumorigenesis of HCC through the induction of mitochondrial injury via OPA1. Our results provide new insights into the pathogenesis of HCC and suggest that OPA1 is a novel therapeutic target in patients with HCC.

Hepatocellular carcinoma (HCC) and hepatic metastases of colon cancers are malignant conditions of the liver that cause significant morbidity and mortality worldwide. Experimental models suggest that both conditions are characterized by epithelial-mesenchymal transition (EMT). Whilst ongoing research efforts aim to definitively clarify its role in human cancer patients, data from experimental models have unraveled a number of potential therapeutic targets as well as markers of prognostic importance. This area of research is generating intense interest amongst both basic scientists and clinicians. Some questions have been answered, but many important issues remain unresolved. We expect that in the near future, studies of human tissues can definitively clarify the role of EMT in the development and progression of human malignant diseases of the liver and that further studies can be carried out to determine how best to target aspects of the process for the treatment of patients with hepatocellular carcinoma and hepatic metastases of colon cancers.

Prostate cancer is the 2nd most common cancer in the world for men. For reasons still unclear, aggressive PCa disproportionately affects males of African ancestry (MoAA). Incidence and mortality rates are highest in MoAA as they have consistently shown a 2.3-3.0-fold higher risk of mortality compared to Caucasian men (CM). This aggressiveness of PCa may be due to specific biologic factors. Located downstream of c-Myc at chromosome 8q24 is PVT1, which encodes miR-1207-3p. Studies have shown that PVT1/MYC cooperation is a fundamental feature in all cancers with 8q24 amplification, and 98% of the 8q24 amplicons contained concurrent amplification of the MYC and PVT1 loci. Moreover, MYC has been linked to PCa aggressiveness and has been reported to be downstream of AR in some PCa. However, the mechanisms regulating c-MYC have never been studied in MoAA. We recently demonstrated that miR-1207-3p directly binds to FNDC1 to regulate a novel FNDC1/FN1/AR pathway upregulated in metastatic prostate cancer (PCa). However, the mechanisms regulating c-Myc in PCa remain unclear, and the relevance of our novel and clinically significant miR-1207-3p molecular pathway in PCa in MoAA is unknown. The aim of this study was to determine if c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. We used qPCR, immunoblotting, RNA pulldown, proliferation, migration, and apoptosis assays to evaluate miR-1207-3p regulation of c-Myc in aggressive PCa in MoAA. Also, miR-1207-3p, FNDC1, FN1, AR, and c-Myc expression was analyzed in prostate tissues (normal = 21; benign = 41; tumor = 26) of patients who received prostatectomy or transrectal ultrasound-guided biopsies at the University College Hospital, Ibadan, Nigeria, a sub-Saharan Black African population. Seventeen patients had tumor tissues with Gleason score ≥ 8. Tissues were collected in compliance with Institutional Review Board-approved protocols. ANOVA, student's t-test, and Tukey post-hoc tests were used for statistical analysis. Prostate tissue analysis revealed that underexpression of miR-1207-3p and the overexpression of FNDC1, FN1, AR, and c-Myc is significantly associated with aggressive PCa in MoAA. Also, miR-1207-3p was underexpressed while FNDC1 and c-MYC were overexpressed in tumors with Gleason score ≥8 in comparison to those with Gleason score 75% in the MoAA-derived indolent E006AA PCa cell line and the MoAA-derived aggressive/castration-resistant E006AA-hT PCa cell line, indicating that c-Myc is downstream of AR. c-Myc expression is higher in the E006AA-hT PCa cell line when compared to the E006AA PCa cell line, suggesting that c-Myc is associated with aggressive PCa. Moreover, NB1207 significantly inhibited migration and induced apoptosis in E006AA and E006AA-hT PCa cell lines. Next, we compared the efficacy of NB1207 in inhibiting proliferation to the commercially available drugs for treatment of CPRC (enzalutamide and abiraterone). NB1207 inhibited proliferation in the CRPC cell line E006AA-hT by nearly 50% while enzalutamide and abiraterone had no effect. In conclusion, miR-1207-3p regulates c-Myc expression via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. miR-1207-3p may be a biomarker for risk stratification in PCa in MoAA. NB1207 has potential for therapeutic targeting of c-Myc for treatment of aggressive PCa in MoAA. Citation Format: Dibash K. Das, Akintunde T. Orunmuyi, Gabriel Olabiyi Ogun, S. Adekola Adebayo, A. Ayo Salako, Adeodat Ilboudo, Cuong Bach, E. O. Olapade-Olaopa, Olorunseun O. Ogunwobi. c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B61.

Many human breast cancers overexpress the E3 ubiquitin ligase MDM2 and its homolog MDMX. The Cancer Genome Atlas (TCGA) shows that high MDM2 and MDMX expression correlates with both estrogen receptor positive (ER+) and triple negative breast cancer (TNBC) subtypes. Overexpression of MDM2 and MDMX can drive breast cancer progression through molecular pathways that do not require wild-type p53 degradation. ER positive breast cancers often express wild-type p53 but 80% of TNBC express mutant p53 (mtp53). It has not been determined how MDM2 and MDMX expression in different sub-types of breast cancer, with mutant p53, influence proliferation and metastasis. We compared MDM2 and MDMX-dependent biological outcomes for mtp53 expressing ER+ T47D (mtp53 L194F) and TNBC cell type MDA-MB-231 (mtp53 R280K). In the ER+ cells no change was detected for real time cell migration or E-cadherin protein levels when MDM2 was knocked down by stable shRNA expression but cell proliferation was reduced. In support of this in vitro data, these MDM2 knockdown cells tested in an orthotopic xenograft model in NSG mice demonstrated no MDM2-mediated change in primary tumor invasiveness but did show a reduced tumor volume. Importantly, in the TNBC MDA-MB-231 cells, knocking down either MDM2 or MDMX did not reduce cell proliferation in vitro but greatly blocked cell migration. In support of this in vitro data, these MDA-MB-231 cells with either MDM2 or MDMX knockdown in NSG mice did not show a reduced primary tumor volume but showed a significant inhibition of the production of circulating tumor cells (CTCs). Our data shows that in different subtypes of breast cancers, MDM2 and MDMX can promote alternative p53-independent biological outcomes. The estrogen-activated MDM2 strongly promotes cell proliferation while MDM2 and MDMX overexpression in TNBC promotes circulating tumor cells and potentially metastasis. Understanding the alternative p53-independent roles of MDM2 and MDMX in ER+ and triple negative breast cancers will provide insight for the development of MDMs-targeted theranostics. Citation Format: Chong Gao, Gu Xiao, Ale Piersiga, Jiangtao Gou, Olorunseun Ogunwobi, Jill Bargonetti. MDM2 and MDMX promote p53-independent initiation of circulating tumor cells from triple negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5188.

Prostate cancer (PCa) is the second most common cancer and third deadliest cancer in American men, yet the only established risk factors are familial genetics, age and race. Men of African Ancestry (moAA) have higher PCa incidence rates when compared to Caucasian men in the United States, which are due to differences in genetic susceptibility variants. Moreover, high mortality rates of PCa are associated with castration-resistant prostate cancer (CRPC) due to maintenance of androgen receptor (AR) signaling in PCa cells following androgen ablation therapy. The 8q24 chromosomal locus is a highly susceptible PCa region that has frequent amplifications of the c-MYC oncogene and downstream PVT1 gene. PVT1 is a long non-protein coding gene that encodes six annotated microRNAs (miRNAs), including microRNA-1205 (miR-1205), yet the function of these miRNAs are poorly understood. To elucidate the role of miR-1205 in PCa, we examined miR-1205 mRNA expression in a cohort of normal (n=22), benign (n=42), and malignant (n=26) histologically confirmed prostatic tissues obtained from prostatectomy or transrectal biopsies of moAA men in Ibadan, Nigeria. One-way ANOVA analysis determined changes in the relative expression of miR-1205 between groups (F(2,87) = 1.153) and a Tukey post hoc test revealed decreased miR-1205 expression in benign (4.61 ± 7.5) and malignant tumors (3.39 ± 3.53) when compared to normal tissues (6.55 ± 9.5). These data suggest that miR-1205 may function as a miRNA tumor suppressor and is characteristic to moAA-associated PCa. To elucidate the molecular mechanism of miR-1205, we examined AR and c-MYC mRNA expression using androgen-dependent LNCaP and CRPC C4-2B and 22RV1 cells. We observed a two-fold decrease of miR-1205 expression and overexpression of AR and c-MYC in C4-2B and 22RV1 cells when compared to LNCaP, suggesting that miR-1205 may regulate AR and c-MYC signaling in CRPC. Next, we identified Fry-like (FRYL) as a putative target using a miSVR computer algorithm and subsequently performed whole transcriptome analysis on prostate tumors and adjacent normal tissue from fourteen PCa patients using the Galaxy web platform. FRYL and AR overexpression was observed in diseased patients suggesting that FRYL may function as an oncogene. Moreover, FRYL was overexpressed in C4-2B and 22RV1 cells when compared to LNCaP, further suggesting a role in CRPC development. C4-2B cells transfected with miR-1205 and the 3'UTR of FRYL in a luciferase expressing vector revealed a significant decrease in luciferase activity when compared to control cells, indicating direct binding of miR-1205 to the 3'UTR of FRYL. These observations strongly suggest that miR-1205 acts as a tumor suppressor that may regulate AR and c-MYC expression, and directly targets the 3'UTR of FRYL in PCa cells. Further understanding the role of miR-1205 regulation of FRYL, AR, and c-MYC signaling may provide novel insights into the molecular mechanisms of CRPC. Citation Format: Michelle K. Naidoo, Dibash K. Das, Adeodat Ilboudo, Akintunde Orunmuyi, Gabriel O. Ogun, S. A. Adebayo, E. O. Olapade-Olaopa, Olorunseun Ogunwobi. MicroRNA-1205 as a tumor suppressor in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 503.

African ancestry is an established nonmodifiable risk factor for aggressive prostate cancer (PCa). The underlying biologic mechanisms are still unclear. We previously demonstrated that exon 9 of PVT1, a long nonprotein coding gene, may be involved in racial disparity in PCa. Using the most recent full-genome variability panel from the 1000 Genomes project, we recently identified a string of 75 SNPs in a 26-kb region spanning PVT1 exons 4A and 4B as consistently showing the highest level of genetic differentiation between African and non-African populations. However, the expression of PVT1 exons 4A, 4B, and 9 in prostate tissues of males of African ancestry (MoAA) has never been investigated. We aimed to determine the expression of PVT1 exons 4A, 4B, and 9 in histologically confirmed normal prostate (n=22), benign tumor prostate (n=35), and malignant tumor prostate tissue (n=28) samples obtained from males who had undergone prostatectomy or transrectal ultrasound-guided biopsy in Nigeria, a sub-Saharan Black African population. Tissues were collected in compliance with Institutional Review Board-approved protocols and histopathologic analysis was performed. RNA extraction, cDNA synthesis, and quantitative-PCR were performed to analyze mRNA expression of PVT1 exon 4A, PVT1 exon 4B, and PVT1 exon 9. There was a statistically significant difference in the expression of PVT1 exon 4A (F(2,61)=9.031, p=0.000); PVT1 exon 4B (F(2,61)=5.294, p=0.004); and PVT1 exon 9 (F(2,61)=3.700, p=0.029) between groups as determined by one-way ANOVA. Tukey post-hoc test revealed mean expression of PVT1 exon 4A = 3.15±0.49 (95% CI [2.13, 4.17]), PVT1 4B = 2.24±0.360 (CI [1.47, 2.95]), and PVT1 exon 9 = 1.644±0.95 (95% CI [1.265, 2.023]) in prostate tumor tissues. The results show an overexpression of PVT1 exon 4A, PVT1 exon 4B, and PVT1 exon 9 in malignant prostate tissue compared with nonmalignant tissue in MoAA. Also, using RNA ISH, PVT1 exon 9 was detected overexpressed primarily in the epithelium of prostate tumor tissue. In conclusion, the results also suggest that (1) the overexpression of PVT1 exon 4A, PVT1 exon 4B, and PVT1 exon 9 is characteristic of PCa in MoAA and (2) overexpression of PVT1 exon 4B and PVT1 exon 9 is specific for PCa, and that PVT1 exon 4B may distinguish between indolent and aggressive PCa in MoAA. Citation Format: Adeodat Ilboudo, Akintunde Orunmuyi, Cuong Bach, Olorunseun Ogunwobi. Overexpression of PVT1 exons 4A, 4B, and 9 is characteristic of aggressive prostate cancer in males of African ancestry [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B36.

Introduction Chromosome 8q24 prostate cancer (PCa) susceptibility region encodes miR-1207–3 p which directly targets fibronectin type III domain containing 1 (FNDC1) to regulate fibronectin (FN1) and subsequently the androgen receptor (AR), and FNDC1/FN1/AR is overexpressed in metastatic PCa (Das et al, Exp Cell Res, 2016). Material and methods Expression of miR-1207–3 p and c-MYC in histologically confirmed normal prostate, benign prostatic hyperplasia (BPH) and PCa from prostatectomy or transrectal ultrasound-guided biopsies was analysed. Molecular mechanisms were elucidated using mCRPC cell lines. Effects of NB1207 and NB5, two novel synthetic analogues of miR-1207–3 p, on AR-V7 (implicated in PCa therapeutic resistance), mCRPC tumour growth in mice were studied. Results and discussions miR-1207–3 p is underexpressed in PCa (0.10±0.02, 95% CI [0.1, 0.2], p=0.000) in comparison to normal prostate (1.02±0.17, 95% CI [0.7, 1.4], p=0.000) and BPH (0.74±0.15, 95% CI [0.4, 1.1] p=0.004). c-MYC was overexpressed in PCa (34.76±8.11, 95% CI [18.1, 51.4], p=0.000; normal: 1.99±0.34, 95% CI [1.3, 2.7]; BPH: 1.01±0.21, 95% CI [0.6, 1.4], p=0.000). miR-1207–3 p was underexpressed by nearly 3-fold in PCa with Gleason score ≥8 versus those with Gleason score Conclusion This study shows potential diagnostic and prognostic value of miR-1207–3 p in mCRPC, and that NB5 and NB1207, novel analogues of miR-1207–3 p, may be candidate therapeutics for mCRPC.

In this review, we will examine various molecular biomarkers for their potential to serve as independent prognostic factors for predicting survival outcome in postoperative patients with progressive intrahepatic cholangiocarcinoma. Specific rodent models of intrahepatic cholangiocarcinoma that mimic relevant cellular, molecular, and clinical features of the human disease are also described, not only in terms of their usefulness in identifying molecular pathways and mechanisms linked to cholangiocarcinoma development and progression, but also for their potential value as preclinical platforms for suggesting and testing novel molecular strategies for cholangiocarcinoma therapy. Last, recent studies aimed at addressing the role of desmoplastic stroma in promoting intrahepatic cholangiocarcinoma progression are highlighted in an effort to underline the potential value of targeting tumor stromal components together with that of cholangiocarcinoma cells as a novel therapeutic option for this devastating cancer.

The majority of cancer-related deaths are caused by the metastasis of the cancer rather than the primary tumor itself. Yet, the underlying mechanisms of cancer metastasis are still unclear. Animal models are essential for elucidating the mechanisms and for evaluating novel strategies for the treatment of metastatic cancers. Here, an in-depth description of a “patient-like” orthotopic syngeneic mouse model for exploring the mechanisms of metastasis of solid organ tumors is provided. The survival surgical implantation of BNL 1ME A.7R.1 mouse hepatocellular carcinoma cells directly into the liver (the organ of origin) of the inbred wild-type immune competent laboratory mouse strain, BALB/c is described. The success and reproducibility of this methodology recommends it for widespread use in elucidating the biological mechanisms of solid organ cancer metastasis.