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Simple Summary: Hypopharyngeal squamous cell carcinoma (HSCC) is a type of cancer with poor prognosis in head and neck tumors. More studies have shown that abnormal expression of lncRNA plays a crucial role in HSCC. Through RIP experiments, we confirmed that NR120519 interacts with KRT17, and the expression of both is closely related to the overall survival of HSCC. Subsequent experiments showed that both NR120519 and KRT17 could regulate the AKT/mTOR pathway and lead to EMT transformation, promoting the progression of HSCC. Therefore, NR120519/KRT17/AKT/mTOR axis has been identified as a new pathway, providing a feasible preliminary basis for future studies. Background: Hypopharyngeal carcinoma is the worst type of head and neck squamous cell carcinoma. It is necessary to identify the key molecular targets related to the carcinogenesis and development of hypopharyngeal carcinoma. Methods: Differentially expressed lncRNAs in hypopharyngeal carcinoma were selected by microarray, and lncRNA-associated proteins were found by RIP assay. Colony formation, CCK-8, wound healing and Transwell assays were performed to detect the effects of lncRNA and its associated protein on cell proliferation and migration in vitro. Downstream pathways of lncRNA and its associated protein were detected by WB. Through a subcutaneous tumor model, the effects of lncRNA and its associated protein on cell proliferation were detected. The expressions of lncRNA and its associated protein in hypopharyngeal cancer tissues were detected by qRT-PCR and immunohistochemistry assays, respectively, and survival analyses were performed by Kaplan-Meier curve. Results: A total of 542 and 265 lncRNAs were upregulated and downregulated in microarrays, respectively. LncRNA NR120519 was upregulated and promoted cell proliferation and migration of hypopharyngeal carcinoma in vitro and cell proliferation in vivo. RIP and WB assays showed that KRT17 was associated with and blocked by NR120519.The silencing of KRT17 promoted cell proliferation and the migration of hypopharyngeal carcinoma in vitro and cell proliferation in vivo by activating the AKT/mTOR pathway and epithelial-mesenchymal transformation (EMT). Finally, the NR120519 high expression and KRT17 low expression groups showed shorter overall survival. Conclusion: NR120519 activated the AKT/mTOR pathway and EMT by blocking KRT17 to promote cell proliferation and the migration of hypopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: At present, the immunotherapy and immune microenvironment of bladder cancer have attracted more and more attention from clinicians and researchers. In this study, the high expression of SULF2 by RNA sequencing of tissues from 90 bladder cancer patients was associated with poor prognosis in patients. We further found that a high expression of SULF2 can promote the polarization of macrophages to M2. In mechanistic studies, we found that SULF2 can promote the secretion of IL-8 through Wnt/β-catenin. IL-8 promotes the transcription of CD163 and CD206 in the microenvironment, ultimately leading to the polarization of macrophages to M2 macrophages. This study elucidates the effect of SULF2 on the polarization of macrophages in the tumor microenvironment. Sulfatase 2 (SULF2) affects the occurrence and development of cancer by regulating HSPG-binding factors. However, the mechanism of SULF2 in bladder cancer (BCa) is unknown. To determine this, we analyzed the RNA sequencing of 90 patients with BCa. The results showed that the expression of SULF2 was closely related to the prognosis of BCa. Moreover, in vivo and in vitro experiments revealed that SULF2 promotes tumor proliferation and invasion. Furthermore, using a mouse orthotopic BCa model and flow cytometric analysis, we identified that SULF2 affects the polarization of macrophages. Mechanism studies clarified that SULF2 promoted the release of HSPG-binding factors, such as IL-8, in the microenvironment through β-catenin. Meanwhile, IL-8 activated the JAK2/STAT3 pathway of macrophages to promote the expression of CD163 and CD206, thereby regulating the polarization of macrophages to the M2-type. Conclusively, these results indicate that SULF2 plays an important role in regulating the microenvironment of BCa and promotes the polarization of macrophages to the M2-type by secreting IL-8, which further deepens the malignant progression of BCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Human Papilloma Virus (HPV) is known to affect thousands globally. HPV infection can act carcinogenically on host cells with expression of the virus's E6 and E7 oncoproteins. Within the United States, roughly 70% of oropharyngeal cancers are thought to be HPV induced. Viral genome integration has been well studied, yet genomic effects of the E6 and E7 proteins on other genetic regions remain relatively unidentified. This study characterizes genomic mutation in HPV-infected HNSCC patients with specific regard to host E6 and E7 expression. Individuals with greater presence of these oncoproteins were found to exhibit a greater average of point mutations, particularly on chromosomes 1, 11, and 17. Greater expression of E6 and E7 also correlates to a lesser number of clustered variation events and fewer repeats of copy number segments. Analysis of the genomic effects of HPV may provide additional insight into the pathogenesis of HNSCC. Human Papilloma Virus (HPV) is highly prevalent within the U.S., with studies estimating that over 80% of individuals will contract the virus in their lifetime. HPV is considered a primary risk factor for the development and progression of oropharyngeal cancers. The impact of the HPV virus's E6 and E7 oncoproteins on cellular signaling pathways and genomic integration has been extensively characterized. Indirect genomic effects; however, remain relatively unidentified. In this study, we analyzed 83 HPV+ Head and Neck Squamous Cell Carcinoma (HNSCC) patients of varying HPV types. Expression counts of the HPV E6 and E7 oncogenes were estimated across samples and correlated with genomic mutational classes. High expression of E6 and E7 oncoproteins was associated with a greater number of total point mutations, especially on chromosomes 1, 11, and 17, which have been implicated in HPV-mediated cancers in previous studies. Samples with high E6 and E7 expression also exhibited more frequent non-clustered structural variation and a lack of clustered variation altogether. Copy number segments were present with fewer number of repeats in high E6 and E7 expression samples, which is known to correlate with decreased expression of affected genes. E6 and E7 expression was associated with increased activity of several cellular pathways associated in oncogenesis and telomere maintenance. In comprehensively characterizing the effects of the HPV oncoproteins on the human genome, potential mechanisms of HNSCC pathogenesis may be further elucidated. [ABSTRACT FROM AUTHOR]

Simple Summary: To date, there has not been adequate research conducted on prostate cancer tumor stem cells, which play an important role in tumor recurrence, invasion, and drug resistance. In this study, we innovatively used a tumor stem cell-associated index (mRNAsi), calculated by a single-class logistic regression machine learning algorithm (OCRL), in combination with multiple databases to identify MBNL1-AS1 as a key lncRNA for prostate cancer stem cells and elucidated via in vivo and in vitro experiments. In addition, the experiments showed that the down-regulation of MBNL1-AS1 promotes the malignance of prostate cancer cell lines through the miR-221-3p/CDKN1B/C-myc axis by stimulating the stemness of tumor stem cells. This provides the basis for theoretical studies of prostate cancer and provides targets for precision therapy. The recurrence, progression, and drug resistance of prostate cancer (PC) is closely related to the cancer stem cells (CSCs). Therefore, it is necessary to find the key regulators of prostate cancer stem cells (PCSCs). Here, we analyzed the results of a single-class logistic regression machine learning algorithm (OCLR) to identify the PCSC-associated lncRNA MBNL1-AS1. The effects of MBNL1-AS1 on the stemness of CSCs was assessed using qPCR, western blot and sphere-forming assays. The role of MBNL1-AS1 in mediating the proliferation and invasion of the PC cell lines was examined using Transwell, wounding-healing, CCK-8, EdU and animal assays. Dual-luciferase and ChIRP assays were used to examine the molecular mechanism of MBNL1-AS1 in PCSCs. MBNL1-AS1 was shown to be negatively correlated with stemness index (mRNAsi), and even prognosis, tumor progression, recurrence, and drug resistance in PC patients. The knockdown of MBNL1-AS1 significantly affected the stemness of the PC cells, and subsequently their invasive and proliferative abilities. Molecular mechanism studies suggested that MBNL1-AS1 regulates CDKN1B through competitive binding to miR-221-3p, which led to the inhibition of the Wnt signaling pathway to affect PCSCs. In conclusion, our study identified MBNL1-AS1 as a key regulator of PCSCs and examined its mechanism of action in the malignant progression of PC. [ABSTRACT FROM AUTHOR]

Simple Summary: Poorly differentiated and anaplastic thyroid cancers respond poorly to surgery, radiation, and hormone therapy. Cancer stem cells play an important role in tumor growth, drug resistance, and recurrence. This study focuses on how the sonic hedgehog (Shh) pathway maintains thyroid cancer stem cell self-renewal and whether it can be targeted for anticancer therapy. The authors report that the Shh pathway regulates the expression of BMI1 and SOX2, two genes involved in stem cell self-renewal, and that targeting the Shh pathway has little effect on thyroid tumor xenografts but can inhibit the growth of tumor xenografts derived from thyroid cancer stem cells. This study advances the knowledge on how thyroid cancer stem cells regenerate and highlights the potential therapeutic values of targeting the Shh pathway. The sonic hedgehog (Shh) pathway plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. We and others have reported earlier that this pathway is highly activated in thyroid cancer. However, its role in thyroid cancer stem cell (CSC) self-renewal and tumor development remains incompletely understood. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and SRY-Box Transcription Factor 2 (SOX2) are two CSC-related transcription factors that have been implicated in promoting CSC self-renewal. The objective of our current investigation was to determine the role of the Shh pathway in regulating BMI1 and SOX2 expression in thyroid cancer and promoting thyroid tumor growth and development. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 reduced BMI1 and SOX2 expression in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines. The opposite results were obtained in cells overexpressing Gli1 or its downstream transcription factor Snail. The Shh pathway regulated SOX2 and BMI1 expression at a transcriptional and post-transcriptional level, respectively. GANT61 treatment suppressed the growth of SW1736 CSC-derived tumor xenografts but did not significantly inhibit the growth of tumors grown from bulk tumor cells. Clinicopathological analyses of thyroid tumor specimens by immunohistochemical (IHC) staining revealed that BMI1 and SOX2 were highly expressed in thyroid cancer and correlated with Gli1 expression. Our study provides evidence that activation of the Shh pathway leads to increased BMI1 and SOX2 expression in thyroid cancer and promotes thyroid CSC-driven tumor initiation. Targeting the Shh pathway may have therapeutic value for treating thyroid cancer and preventing recurrence. [ABSTRACT FROM AUTHOR]

Simple Summary: While the intratumor microbiome has been largely unexplored in relation to prostate cancer development, our research shows that microbes may play an anti-tumor or pro-tumor role to significantly alter clinical course in prostate cancer patients. We found that the presence and absence of specific microbes are strongly correlated with known biomarkers of prostate cancer, including increased androgen receptor expression, prostate-specific antigen level, immune-associated gene dysregulation, stem-cell related gene overexpression, cancer pathways, and known chromosomal alterations. Our results provide important insight on potential mechanisms by which intratumor microbes may greatly contribute to prostate cancer progression and prognosis. We hope our results can be validated in future studies, and the key microbes that we identified can be used as effective targets for more specialized prebiotic and probiotic treatments for prostate cancer. Although 1 in 9 American men will receive a diagnosis of prostate cancer (PC), most men with this diagnosis will not die from it, as most PCs are indolent. However, there is a subset of patients in which the once-indolent PC becomes metastatic and eventually, fatal. In this study, we analyzed microbial compositions of intratumor bacteria in PC to determine the influence of the microbiome on metastatic growth. Using large-scale RNA-sequencing data and corresponding clinical data, we correlated the abundance of microbes to immune pathways and PC risk factors, identifying specific microbes that either significantly deter or contribute to cancer aggressiveness. Interestingly, most of the microbes we found appeared to play anti-tumor roles in PC. Since these anti-tumor microbes were overrepresented in tumor samples, we believe that microbes thrive in the tumor microenvironment, outcompete cancer cells, and directly mitigate tumor growth by recruiting immune cells. These include Listeria monocytogenes, Methylobacterium radiotolerans JCM 2831, Xanthomonas albilineans GPE PC73, and Bradyrhizobium japonicum, which are negatively correlated with Gleason score, Tumor-Node-Metastasis (TNM) stage, prostate-specific antigen (PSA) level, and Androgen Receptor (AR) expression, respectively. We also identified microbes that contribute to tumor growth and are positively correlated with genomic alterations, dysregulated immune-associated (IA) genes, and prostate cancer stem cells (PCSC) genes. [ABSTRACT FROM AUTHOR]

Immunotherapy has emerged in recent years as arguably the most effective treatment for advanced hepatocellular carcinoma (HCC), but the failure of a large percentage of patients to respond to immunotherapy remains as the ultimate obstacle to successful treatment. Etiology-associated dysregulation of immune-associated (IA) genes may be central to the development of this differential clinical response. We identified immune-associated genes potentially dysregulated by alcohol or viral hepatitis B in HCC and validated alcohol-induced dysregulations in vitro while using large-scale RNA-sequencing data from The Cancer Genome Atlas (TCGA). Thirty-four clinically relevant dysregulated IA genes were identified. We profiled the correlation of all genomic alterations in HCC patients to IA gene expression while using the information theory-based algorithm REVEALER to investigate the molecular mechanism for their dysregulation and explore the possibility of genome-based patient stratification. We also studied gene expression regulators and identified multiple microRNAs that were implicated in HCC pathogenesis that can potentially regulate these IA genes' expression. Our study identified potential key pathways, including the IL-7 signaling pathway and TNFRSF4 (OX40)- NF-κB pathway, to target in immunotherapy treatments and presents microRNAs as promising therapeutic targets for dysregulated IA genes because of their extensive regulatory roles in the cancer immune landscape. [ABSTRACT FROM AUTHOR]

Among all breast cancer types, basal-like breast cancer (BLBC) represents an aggressive subtype that lacks targeted therapy. We and others have found that receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in BLBC and other types of cancer and that ROR1 is significantly correlated with patient prognosis. In addition, using primary patient-derived xenografts (PDXs) and ROR1-knockout BLBC cells, we found that ROR1+ cells form tumors in immunodeficient mice. We developed an anti-ROR1 immunotoxin and found that targeting ROR1 significantly kills ROR1+ cancer cells and slows down tumor growth in ROR1+ xenografts. Our bioinformatics analysis revealed that ROR1 expression is commonly associated with the activation of FGFR-mediated signaling pathway. Further biochemical analysis confirmed that ROR1 stabilized FGFR expression at the posttranslational level by preventing its degradation. CRISPR/Cas9-mediated ROR1 knockout significantly reduced cancer cell invasion at cellular levels by lowering FGFR protein and consequent inactivation of AKT. Our results identified a novel signaling regulation from ROR1 to FGFR and further confirm that ROR1 is a potential therapeutic target for ROR1+ BLBC cells. [ABSTRACT FROM AUTHOR]