Search

Abnormalities in mucosal immunity are involved in the onset and progression of ulcerative colitis (UC), resulting in a high incidence of colorectal cancer (CRC). While high-mobility group box-1 (HMGB1) is overexpressed during colorectal carcinogenesis, its role in UC-related carcinogenesis remains unclear. In the present study, we investigated the role of HMGB1 in UC-related carcinogenesis and sporadic CRC. Both the azoxymethane colon carcinogenesis and dextran sulfate sodium colitis carcinogenesis models demonstrated temporal increases in mucosal HMGB1 levels. Activated CD8+ cells initially increased and then decreased, whereas exhausted CD8+ cells increased. Additionally, we observed increased regulatory CD8+ cells, decreased naïve CD8+ cells, and decreased mucosal epithelial differentiation. In the in vitro study, HMGB1 induced energy reprogramming from oxidative phosphorylation to glycolysis in CD8+ cells and intestinal epithelial cells. Furthermore, in UC dysplasia, UC-related CRC, and hyperplastic mucosa surrounding human sporadic CRC, we found increased mucosal HMGB1, decreased activated CD8+ cells, and suppressed mucosal epithelial differentiation. However, we observed increased activated CD8+ cells in active UC mucosa. These findings indicate that HMGB1 plays an important role in modulating mucosal immunity and epithelial dedifferentiation in both UC-related carcinogenesis and sporadic CRC.

Background: We previously reported Minichromosome maintenance 4 (MCM4) overexpression in gastric cancer. However, the clinicopathological significance of MCM4 in urothelial carcinoma (UC) has not been investigated. To clarify the clinicopathological significance of MCM4 in UC, we investigated MCM4 expression with immunohistochemistry (IHC)., Methods: We analyzed the expression and distribution of MCM4 in 124 upper tract urothelial carcinoma (UTUC) samples by IHC. Additionally, using 108 urine samples, we analyzed MCM4 Immunocytochemistry (ICC) expression in urine cytology., Results: In normal urothelium, MCM4 expression was weak or absent. Meanwhile, the strong nuclear expression of MCM4 was observed in UTUC tissues, and it was detected in 77 (62%) of a total of 124 UTUC cases. MCM4-positive UTUC cases were associated with nodular/flat morphology, high grade, high T stage, and poor prognosis. Moreover, MCM4 expression was significantly higher in the invasive front than in the tumor surface. Similar results were also obtained in TCGA bladder cancer cohort. Additionally, MCM4 expression was associated with high expression of Ki-67, HER2, EGFR, and p53 in UTUC. Among representative cancer-related molecules, MCM4 had an independent predictive value for progression-free survival and high-grade UC. ICC for MCM4 was also performed on urine cytology slides and showed that the nuclear expression of MCM4 was more frequently found in UC cells than in non-neoplastic cells. The diagnostic accuracy of urine cytology was improved by combining MCM4 immunostaining with cytology., Conclusion: These results suggest that MCM4 might be a useful predictive biomarker for high-grade histology, tumor progression and poor prognosis in UC. Moreover, ICC for MCM4 might be helpful for UC detection as additional markers in the cytomorphology-based diagnosis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: Upper tract urothelial carcinoma (UTUC) can be divided into renal pelvis tumor (RPT) and ureteral tumor (UT) based on the tumor origin. This study aimed to evaluate the efficacy of neoadjuvant chemotherapy with gemcitabine and cisplatin (NAC-GC) in terms of the pathological outcomes and oncological prognoses in patients with UTUC. We also compared its efficacy between RPT and UT., Materials and Methods: Patients who underwent radical nephroureterectomy for clinical T (cT)3N0M0 UTUC between 1999 and 2021 were included. Patients who underwent NAC-GC and those who did not were included in the NAC-GC and non-NAC-GC groups, respectively. Based on the tumor origin, we divided patients with UTUC into RPT and UT groups. Oncological prognosis was assessed using progression-free survival (PFS) and overall survival., Results: Of 44 patients, 20 (45.5%) and 24 (54.5%) patients were in the NAC-GC and non-NAC-GC groups, respectively. The NAC-GC group had significantly lower pathological T stage and negative lymphovascular invasion (LVI), and a better PFS (p < .05) compared to those in the non-NAC-GC group. Among patients with RPT, the NAC-GC group had significantly negative LVI and better PFS than the non-NAC-GC group (p < .05). In contrast, in patients with UT, the NAC-GC group had no significant difference in pathological outcomes, and no significant difference in oncological prognosis was observed between the NAC-GC and non-NAC-GC groups., Conclusion: NAC-GC improves both pathological outcomes and oncological prognosis in patients with cT3N0M0 UTUC. With regard to tumor location, RPT has better pathological outcomes and oncological prognoses than UT.

A novel large neutral amino acid transporter 1 (LAT1)-specific inhibitor, JPH203, is expected to cause cancer-specific starvation and possess anti-tumor effects; however, its anti-tumor mechanism for colorectal cancer (CRC) remains unclear. We analyzed LAT family gene expressions in public databases using UCSC Xena and evaluated LAT1 protein expression using immunohistochemistry in 154 cases of surgically resected CRC. We also evaluated mRNA expression using polymerase chain reaction in 10 CRC cell lines. Furthermore, JPH203 treatment experiments were conducted in vitro and in vivo using an allogeneic immune-responsive mouse model with abundant stroma created via the orthotopic transplantation of the mouse-derived CRC cell line CT26 and mesenchymal stem cells. The treatment experiments were followed by comprehensive gene expression analyses with RNA sequencing. Database analyses and immunohistochemistry research on clinical specimens revealed that LAT1 expression was cancer-dominant, and its increase was accompanied by tumor progression. In vitro, JPH203 was effective in an LAT1 expression-dependent manner. In vivo, JPH203 treatment considerably reduced tumor size and metastasis, and RNA sequencing-based pathway analysis showed that not only tumor growth and amino acid metabolism pathways, but also stromal activation-related pathways were suppressed. The results of the RNA sequencing were validated in the clinical specimens, as well as both in vitro and in vivo. LAT1 expression in CRC plays an important role in tumor progression. JPH203 may inhibit the progression of CRC and tumor stromal activity.

Although radiotherapy is the standard treatment for Helicobacter pylori (Hp)-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma, eradication therapy using antibiotics and an acid secretion suppressor can sometimes induce complete remission. We explored predictive markers for the response to eradication therapy for gastric MALT lymphoma that were negative for both API2-MALT1 and Hp infection using comprehensive RNA sequence analysis. Among 164 gastric MALT lymphoma patients who underwent eradication therapy as primary treatment, 36 were negative for both the API2-MALT1 fusion gene and Hp infection. Based on eradication therapy efficacy, two groups were established: complete response (CR) and no change (NC). The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that cancer-related genes and infection-related genes were highly expressed in the NC and CR groups, respectively. Based on this finding and transcription factor, gene ontology enrichment, and protein-protein interaction analyses, we selected 16 candidate genes for predicting eradication therapy efficacy. Real-time PCR validation in 36 Hp-negative patients showed significantly higher expression of olfactomedin-4 ( OLFM4 ) and the Nanog homeobox ( NANOG ) in the CR and NC groups, respectively. OLFM4 and NANOG could be positive and negative predictive markers, respectively, for eradication therapy efficacy against gastric MALT lymphoma that is negative for both API2-MALT1 and Hp infection.

Background: We sought to identify an optimal combination of survival risk stratification markers in patients with pathological (p) stage II/III gastric cancer (GC) after curative resection., Methods: We measured the expression levels of 127 genes in pStage II/III GC tissues of two patient cohorts by quantitative polymerase chain reaction (qPCR) and the expression of 1756 proteins between two prognosis (good and poor) groups by proteomic analysis to identify candidate survival stratification markers. Further, immunohistochemistry (IHC) using tumor microarrays (TMAs) in another cohort of patients was performed to identify an optimal biomarker combination for survival stratification in GC patients., Results: secreted protein acidic and rich in cysteine (SPARC), erb-b2 receptor tyrosine kinase 2 (ERBB2), inhibin subunit beta A (INHBA), matrix metallopeptidase-11 (MMP11), tumor protein p53 (TP53), and platelet-derived growth factor receptor-beta (PDGFRB) were identified as candidate biomarkers from qPCR analysis, and SPARC and galectin-10 were obtained from the proteomic analysis. The combination of PDGFRB, INHBA, MMP11, and galectin-10 was identified as the optimal combination of survival risk stratification markers., Conclusions: A combination of four proteins in GC tissues may serve as useful survival risk stratification markers in patients with pStage II/III GC following curative resection. Our results may facilitate future multicenter prospective clinical trials.

Background: Bladder cancer (BC) is the 10th most common cancer in the world. BC with muscle invasion results in a poor prognosis and is usually fatal. Cancer cell metabolism has an essential role in the development and progression of tumors. Expression of tryptophan 2,3-dioxygenase (TDO2) is associated with tumor progression and worse survival in some other cancers. However, no studies have been performed to uncover the biofunctional roles of TDO2 in BC., Aim: This study aim to investigate the clinicopathologic significance of TDO2 in BC., Methods and Results: TDO2 expression was evaluated by qRT-PCR and immunohistochemistry in an integrated analysis with the Cancer Genome Atlas (TCGA) and other published datasets. TDO2 overexpression was significantly associated with T classification, N classification, and M classification, tumor stage, recurrence, and basal type, and with the expression of CD44 and aldehyde dehydrogenase 1 (ALDH1) in BC. High TDO2 expression correlated with poor outcome of BC patients. Using BC cell lines with knockdown and forced expression of TDO2, we found that TDO2 was involved in the growth, migration, and invasiveness of BC cells. Moreover, TDO2 was found to be crucial for spheroid formation in BC cells. Importantly, TDO2 promoted BC cells resistance to cetuximab through integration of the EGFR pathway., Conclusion: Our results indicate that TDO2 might take an essential part in BC progression and could be a potential marker for targeted therapy in BC., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Competing Interests: The authors have no conflicts of interest to declare.

Kinesin family member C1 ( KIFC1 ), a minus end-directed motor protein, is reported to play an essential role in cancer. This study aimed to analyze KIFC1 expression and examine KIFC1 involvement in cisplatin resistance in bladder cancer (BC). Immunohistochemistry showed that 37 of 78 (47.4%) BC cases were positive for KIFC1 . KIFC1 -positive cases were associated with high T stage and lymph node metastasis. Kaplan-Meier analysis showed that KIFC1 -positive cases were associated with poor prognosis, consistent with the results from public databases. Molecular classification in several public databases indicated that KIFC1 expression was increased in basal type BC. Immunohistochemistry showed that KIFC1 -positive cases were associated with basal markers 34βE12, CK5 and CD44. KIFC1 expression was increased in altered TP53 compared to that in wild-type TP53 . Immunohistochemistry showed that KIFC1 -positive cases were associated with p53-positive cases. P53 knockout by CRISPR-Cas9 induced KIFC1 expression in BC cell lines. Knockdown of KIFC1 by siRNA increased the sensitivity to cisplatin in BC cells. Kaplan-Meier analysis indicated that prognosis was poor among KIFC1 -positive BC patients treated with cisplatin-based chemotherapy. Immunohistochemistry showed that KIFC1 -positive cases were associated with PD-L1-positive cases. High KIFC1 expression was associated with a favorable prognosis in patients treated with atezolizumab from the IMvigor 210 study. These results suggest that KIFC1 might be a promising biomarker and therapeutic target in BC.

Background/aim: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study examined the potential role of p53 in sunitinib resistance and as a predictive marker in mRCC., Materials and Methods: We analysed the effects of p53 knockout on sunitinib resistance. p53 expression in 53 mRCC patients receiving first-line sunitinib was determined immunohistochemically. We performed in silico analysis to examine the predictive value of p53 in mRCC., Results: WST-1 assays showed that p53 knockout decreased sensitivity to sunitinib. Sunitinib and nutlin-3 together suppressed cell growth. Immunohistochemistry revealed 11 p53-positive cases among 53 patients with mRCC. Kaplan-Meier analysis showed that p53-positive cases tended to be associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, TP53 mutation was significantly associated with poor PFS after sunitinib treatment., Conclusion: p53 may be involved in sunitinib resistance and represent a valuable marker for sunitinib treatment in mRCC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Although docetaxel (DTX) confers significant survival benefits in patients with castration-resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S-phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin-positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan-Meier analysis showed that high claspin expression was related to poor prostate-specific antigen (PSA) relapse-free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse-free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX-resistant DU145 (DU145-DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145-DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Tryptophan 2,3-dioxygenase (TDO2) is the primary enzyme catabolizing tryptophan. Several lines of evidence revealed that overexpression of TDO2 is involved in anoikis resistance, spheroid formation, proliferation, and invasion and correlates with poor prognosis in some cancers. The aim of this research was to uncover the expression and biofunction of TDO2 in renal cell carcinoma (RCC)., Methods: To show the expression of TDO2 in RCC, we performed qRT-PCR and immunohistochemistry in integration with TCGA data analysis. The interaction of TDO2 with PD-L1, CD44, PTEN, and TDO2 expression was evaluated. We explored proliferation, colony formation, and invasion in RCC cells line affected by knockdown of TDO2., Results: RNA-Seq and immunohistochemical analysis showed that TDO2 expression was upregulated in RCC tissues and was associated with advanced disease and poor survival of RCC patients. Furthermore, TDO2 was co-expressed with PD-L1 and CD44. In silico analysis and in vitro knockout of PTEN in RCC cell lines revealed the ability of PTEN to regulate the expression of TDO2. Knockdown of TDO2 suppressed the proliferation and invasion of RCC cells., Conclusion: Our results suggest that TDO2 might have an important role in disease progression and could be a promising marker for targeted therapy in RCC. (199 words).

Background: Gastric cancers (GCs) are still one of the leading causes of cancer-related mortality. The histological and molecular features of GC may differ widely from area to area within the same tumor. Intratumoral heterogeneity has been considered a major obstacle to an efficient diagnosis and successful molecular treatment., Methods: We selected and reevaluated 842 GC cases and analyzed the relationship between numbers or composites of histological patterns within tumors, and clinicopathological parameters in mucosal and invasive areas. In addition, we searched for the GC-associated molecules or molecular subtypes marking histological diversities., Results: GC cases with more histological numbers or mixed types in invasive areas showed significantly higher T grade and staging, whereas those in mucosal areas did not show any significant associations. GCs with histological diversities showed poorer prognosis and characteristically expressed cancer stem cell-related molecules (CD44, CD133 or ALDH1) and receptor tyrosine kinase molecules (HER2, EGFR or c-MET) as well as Helicobacter pylori infection. Expressions of CD44, HER2, c-MET, laminin 5·2 or retained E-cadherin in mucosal areas were predictive of more histological numbers and mixed types in invasive areas. In addition, the chromosomal instability subtype of GC showed significant associations with more histological numbers and mixed histological type, whereas the genomic stability subtype of GC showed a significant relationship with pure type., Conclusions: We displayed the relationship between histological diversity and molecular features in GC, and we hope that the present data can contribute to the early diagnosis and prevention, and effective treatment of GC.

Background/aim: Glioma-associated oncogene 1 (GLI1) is an important transcription factor in the hedgehog signalling pathway and tumour formation. We evaluated the clinical significance of GLI1 expression as a prognostic factor in patients with locally advanced gastric cancer (GC)., Patients and Methods: GLI1 expression levels were measured by quantitative real-time polymerase chain reaction analysis of cancerous and adjacent normal mucosa specimens obtained from 142 patients with Stage II/III GC administered adjuvant chemotherapy with S-1 after curative resection. The associations of GLI1 expression with clinicopathological features and survival were evaluated., Results: Clinicopathological features and GLI1 expression showed no association. Overall survival was significantly poorer in the high compared to the low GLI1 expression group (p=0.04). Multivariate analysis revealed that GLI1 expression was a significant independent prognostic factor [p=0.019, hazard ratio (HR)=1.94, 95% confidence interval (CI)=1.70-3.38]., Conclusion: GLI1 expression may be a useful prognostic marker in patients with locally advanced GC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

BRAF V600E mutation accounts for up to 90% of all BRAF mutations in human colorectal cancer (CRC), and constitutively activates the MEK-MAPK pathway. It is recognized that neutralizing mAbs for epidermal growth factor receptor alone are not effective for CRC with BRAF V600E mutation. Therefore, there is increasing interest in identification of the possible therapeutic targets in downstream of BRAF mutation in CRCs. To address this, we studied genome engineered mouse models for colonic neoplasia that has Braf V600E mutation on the basis of Apc inactivation, induced in 2 distinct Cre mouse models, CDX2P-G22Cre and CDX2P-CreER T2 mice. We carried out oligonucleotide microarray analysis for colonic neoplasia generated in these mouse models, and compared gene expression profiles among Kras/Braf WT, Kras-mutated, and Braf-mutated mouse colon tumors to seek new molecular targets corresponding to the KRAS-BRAF-MAPK axis. We found that the expression of the growth regulation by estrogen in breast cancer protein 1 (Greb1) was the most upregulated gene in Braf-mutated mouse tumors compared to Kras/Braf WT counterparts. The silencing of GREB1 significantly reduced the proliferation and tumorigenesis of CRC cell lines, whereas the overexpression of GREB1 promoted cell proliferation. Although GREB1 was first identified as a hormone-responsive gene mediating estrogen-stimulated cell proliferation in endometriosis, breast, and ovarian cancers, these results suggest that RAS-RAF-MAPK signaling upregulates GREB1 expression in CRC, resulting in cellular proliferation. Thus, GREB1 is a possible therapeutic target for CRCs with Braf V600E mutation., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Renal cell carcinoma (RCC) is one of the most common human cancers. We previously reported that claspin is a key regulator in the progression of gastric cancer, and it likely plays an important role in cancer stem cells of gastric cancer. However, the significance of claspin in RCC has not been examined. First, we analyzed the expression and distribution of claspin in 95 RCC cases by immunohistochemistry. In the nonneoplastic kidney, the staining of claspin was either weak or absent, whereas RCC tissue showed nuclear staining. In total, claspin expression was detected in 45 (47%) of 95 RCC cases. The claspin staining appeared relatively stronger in high nuclear grade RCC than in low nuclear grade RCC. Claspin-positive RCC cases were associated with higher T grade, tumor stage, nuclear grade, vein invasion, and poorer prognosis. CLSPN siRNA treatment decreased RCC cell proliferation. The levels of phosphorylated Erk and Akt were lower in CLSPN siRNA-transfected RCC cells than in control cells. In addition, claspin was coexpressed with CD44, epidermal growth factor receptor, p53, and programmed death ligand-1. These results suggest that claspin plays an important role in tumor progression in RCC and might be a prognostic marker and novel therapeutic target molecule., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Endothelial cell-specific molecule-1 (ESM-1) is a soluble proteoglycan which has important role in various biological events. We investigated the impact of the ESM-1 expression in cancer tissues on outcomes in stage II/III gastric cancer patients who received adjuvant S-1 chemotherapy., Patients and Methods: The ESM-1 mRNA expression in cancerous tissues and adjacent normal mucosa from 253 patients was measured. The associations between the ESM-1 gene expression and the survival and clinicopathological features were investigated., Results: A significant association was observed between high ESM-1 expression and undifferentiated adenocarcinoma. The overall survival curve was significantly lower in patients with high ESM-1 expression than in those with low expression (p=0.005). High ESM-1 expression was a significant independent prognosticator (HR=2.291, p=0.007)., Conclusion: ESM-1 gene expression in cancerous tissues is an important prognosticator in stage II/III gastric cancer patients who received adjuvant S-1 chemotherapy., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The role of metastasis-related genes in cisplatin (CDDP) chemoresistance in gastric cancer is poorly understood. Here, we examined the expression of four metastasis-related genes (namely, c-met , HMGB1 , RegIV , PCDHB9 ) in 39 cases of gastric cancer treated with neoadjuvant therapy with CDDP or CDDP+5-fluorouracil and evaluated its association with CDDP responsiveness. Comparison of CDDP-sensitive cases with CDDP-resistant cases, the expression of c-met, HMGB1, and PCDHB9 was correlated with CDDP resistance. Among them, the expression of HMGB1 showed the most significant correlation with CDDP resistance in multivariate analysis. Treatment of TMK-1 and MKN74 human gastric cancer cell lines with ethyl pyruvate (EP) or tanshinone IIA (TAN), which are reported to inhibit HMGB1 signaling, showed a 4-5-fold increase in inhibition by CDDP. Treatment with EP or TAN also suppressed the expression of TLR4 and MyD88 in the HMGB1 signal transduction pathway and suppressed the activity of NFκB in both cell lines. These results suggest that the expression of these cancer metastasis-related genes is also related to anticancer drug resistance and that suppression of HMGB1 may be particularly useful for CDDP sensitization.

Background/aim: The KIAA1199 gene has been associated with cancer-cell proliferation, but its functions remain poorly studied. Here, we examined the clinical significance of the KIAA1199 mRNA levels in locally advanced gastric cancer (GC). Materials and Methods/Results: Using samples from 254 patients with stage II/III GC, we found significantly higher KIAA1199 levels in cancerous tissues compared to adjacent normal mucosa (ANM). There was no significant relationship between KIAA1199 expression and clinical features. Although overall survival rates (OSR) of patients, who underwent surgery did not correlate with KIAA1199 expression, patients who underwent adjuvant chemotherapy with S-1 and had high KIAA1199 levels displayed significantly lower OSR. KIAA1199 knock down (KIAA1199-KD) suppressed proliferation, invasiveness, and sensitivity of GC cells to 5-fluorouracil (5-FU)., Conclusion: KIAA1199 expression appears to be a promising prognostic marker in patients with locally advanced GC, who underwent postoperative adjuvant chemotherapy with S-1. KIAA1199 may represent a novel target for GC pharmacotherapy., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The PRKCI gene encodes Protein kinase C iota. The overexpression of protein kinase C iota is associated with poor outcomes in patients with gastric and other cancers, but the role of the PRKCI gene in gastric cancer is not fully understood. Thus, we evaluated the clinical significance of PRKCI gene expression in gastric cancer., Materials and Methods: PRKCI mRNA expression levels in cancerous tissues and adjacent normal mucosa from 398 patients with gastric cancer were measured. Relationships between PRKCI gene expression and clinicopathological characteristics and outcomes were examined., Results: Overall survival was lower in patients with a high expression of PRKCI than in those with low expression (p=0.016). No other relationships were observed. A high PRKCI expression was found to be an independent prognostic factor (p=0.036, HR=1.44, 95%CI=1.02-2.02)., Conclusion: PRKCI gene expression in cancerous tissue might be a useful prognostic factor in patients with gastric cancer after gastrectomy., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Although synbiotics may be effective in maintaining remission of inflammatory bowel disease, their anticarcinogenic effects are still debated. To address this issue, we evaluated the effects of synbiotics, probiotics, and prebiotics on tumorigenesis using a CDX2P-Cre; Apc+/flox mouse model harboring a colon-specific Apc knock out, which develops adenoma and adenocarcinoma of the colon. Dextran sodium sulfate (DSS)-administration promoted colonic tumor development in CDX2P-Cre; Apc+/flox mice, and these tumors were associated with loss of Apc heterozygosity, as confirmed by observation of well-differentiated adenocarcinomas with β-catenin accumulation in tumor cell cytoplasm. Synbiotics-treatment suppressed dextran sodium sulfate-induced colitis in CDX2P-Cre; Apc+/flox mice, thereby reducing mortality, and inhibited tumorigenesis accelerated by DSS-administration. Conversely, neither probiotics nor prebiotics had any effect on inflammation and tumorigenesis. Lactobacillus casei and Bifidobacterium breve were detected in the fecal microbiota of probiotics-treated mice. Synbiotics-treatment suppressed DSS-induced expression of IL-6, STAT-3, COX-2, and TNF-α gene transcripts in normal colonic epithelium, indicating the possibility of suppressing tumor development. Importantly, these genes may be potential therapeutic targets in inflammation-associated colon cancer., Competing Interests: The authors have declared that no competing interests exist.

Background/aim: Colorectal adenoma is well known as a precursor lesion of colorectal adenocarcinoma (ADC). We recently reported the significance of CD204 (+) tumor-associated macrophages (TAMs), a vital component of the tumor microenvironment, in the carcinoma development of gastric adenoma. The aim of the present study was to clarify the roles of TAM in the malignant transformation of colorectal adenoma., Materials and Methods: We immunohistochemically assessed the TAM number in 88 tubular or tubulovillous adenomas that were classified into L (low-grade adenomas) or H (high-grade adenomas)., Results: Larger adenoma size, higher frequency of villous structure, loss of proliferation polarity, p53 expression, larger TAM numbers and larger microvessel density (MVD) were detected in Group H than in Group L adenomas. Positive relations were observed between TAM and MVD, proliferation polarity and the expression of p53., Conclusion: CD204 (+) TAM is a novel component in the malignant transformation of colorectal adenoma., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Kinesin family member C1 (KIFC1) is a minus end-directed motor protein that plays an essential role in centrosome clustering. Previously, we reported that KIFC1 is involved in cancer progression in prostate cancer (PCa). We designed this study to assess the involvement of KIFC1 in docetaxel (DTX) resistance in PCa and examined the effect of KIFC1 on DTX resistance. We also analyzed the possible role of a KIFC1 inhibitor (CW069) in PCa. We used DTX-resistant PCa cell lines in DU145 and C4-2 cells to analyze the effect of KIFC1 on DTX resistance in PCa. Western blotting showed that KIFC1 expression was higher in the DTX-resistant cell lines than in the parental cell lines. Downregulation of KIFC1 re-sensitized the DTX-resistant cell lines to DTX treatment. CW069 treatment suppressed cell viability in both parental and DTX-resistant cell lines. DTX alone had little effect on cell viability in the DTX-resistant cells. However, the combination of DTX and CW069 significantly reduced cell viability in the DTX-resistant cells, indicating that CW069 re-sensitized the DTX-resistant cell lines to DTX treatment. These results suggest that a combination of CW069 and DTX could be a potential strategy to overcome DTX resistance., Competing Interests: The authors declare no conflict of interest.

Background: The transcribed ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs that are absolutely conserved across species and are involved in carcinogenesis in some cancers. However, the expression and biological role of T-UCRs in renal cell carcinoma (RCC) remain poorly understood. This study aimed to examine the expression and functional role of Uc.416 + A and analyze the association between Uc.416 + A and epithelial-to-mesenchymal transition in RCC., Methods: Expression of Uc.416 + A in 35 RCC tissues, corresponding normal kidney tissues and 13 types of normal tissue samples was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). We performed a cell growth and migration assay in RCC cell line 786-O transfected with negative control and siRNA for Uc.416 + A. We evaluated the relation between Uc.416 + A and miR-153, which has a complimentary site of Uc.416 + A., Results: qRT-PCR analysis revealed that the expression of Uc.416 + A was higher in RCC tissues than that in corresponding normal kidney tissues. Inhibition of Uc.416 + A reduced cell growth and cell migration activity. There was an inverse correlation between Uc.416 + A and miR-153. Western blot analysis showed Uc.416 + A modulated E-cadherin, vimentin and snail. The expression of Uc.416 + A was positively associated with the expression of SNAI1, VIM and inversely associated with the expression of CDH1., Conclusions: The expression of Uc.416 + A was upregulated in RCC and especially in RCC tissues with sarcomatoid change. Uc.416 + A promoted epithelial-to-mesenchymal transition through miR-153. These results suggest that Uc.416 + A may be a promising therapeutic target.

Aim: Immunotherapies blocking the CD47-SIRPα pathway by targeting CD47 enhance macrophage phagocytosis of neoplastic cells in mouse models. As SIRPα exhibits relatively restricted tissue expression, SIRPα antagonists may be better tolerated than agents targeting CD47, which is ubiquitously expressed in many tissues. Here, we investigated the therapeutic impact of monoclonal antibodies (mAbs) against CD47 and/or SIRPα on gastroenterological tumors in syngeneic immunocompetent mouse models., Methods: We used in vitro and in vivo phagocytosis assays in C57BL/6J (B6) mice to investigate anti-CD47/SIRPα mAb effects on Hepa1-6 and CMT93 originating from B6 mice. The influence of these mAbs on macrophage transmigration was also assessed. To investigate anti-SIRPα mAb therapy-induced inhibitory effects on sporadic colon cancer growth, we used a CDX2P9.5-NLS Cre;APC + /FLOX ( CPC-APC ) mouse model., Results: Systemic anti-SIRPα mAb administration significantly increased Hepa1-6 and CMT93 cell susceptibility to macrophage phagocytosis, both in vitro and in vivo. Conversely, similarly administered anti-CD47 mAb did not promote macrophage phagocytosis of target cells, whereas cells incubated with anti-CD47 mAb prior to inoculation were more susceptible to macrophage phagocytosis. In vitro cell migration assays revealed that binding with anti-CD47 mAb inhibited macrophage transmigration. Anti-SIRPα mAb treatment inhibited tumor progression in CPC-APC mice and significantly improved overall survival. Anti-CD47 mAb administration in vivo eliminated the phagocytosis-promoting CD47 blockade effect, probably by inhibiting macrophage transmigration/chemotaxis. In contrast, anti-SIRPα mAb exhibited enhanced macrophage phagocytic activity and marked anti-tumor effects against gastroenterological malignancies., Conclusion: SIRPα mAb augmentation of macrophage phagocytic activity may represent an effective treatment strategy for human gastrointestinal tumors.

Accumulating evidence suggests that a unique set of receptor tyrosine kinases, known as discoidin domain receptors (DDRs), plays a role in cancer progression by interacting with the surrounding collagen matrix. In this study, we investigated the expression and role of DDR1 in human gastric cancer metastasis. Proliferation, migration, invasion, and tube formation assays were conducted in DDR1-expressing MKN74 gastric cancer cells and corresponding DDR1-silenced cells. The effects of DDR1 on tumor growth and metastasis were examined in orthotopically implanted and experimental liver metastasis models in nude mice. The expression of DDR1 in surgical specimens was analyzed by immunohistochemistry. DDR1 was expressed in human gastric cancer cell lines, and its expression in human gastric tumors was associated with poor prognosis. Among seven gastric cancer cell lines, MKN74 expressed the highest levels of DDR1. DDR1-silenced MKN74 cells showed unaltered proliferation activity. In contrast, migration, invasion, and tube formation were significantly reduced. When examined in an orthotopic nude mouse model, DDR1-silenced implanted tumors significantly reduced angiogenesis and lymphangiogenesis, thereby leading to reductions in lymph node metastasis and liver metastasis. In a model of experimental liver metastasis, DDR1-silenced cells almost completely inhibited liver colonization and metastasis. DDR1 deficiency led to reduced expression of the genes encoding vascular endothelial growth factor (VEGF)-A, VEGF-C, and platelet-derived growth factor-B. These results suggest that DDR1 is involved in gastric cancer tumor progression and that silencing of DDR1 inhibits multiple steps of the gastric cancer metastasis process., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aim: Gastric cancer (GC) is one of the most common malignancies worldwide. Gremlin1 is an antagonist of bone morphogenetic proteins that plays a critical role in several biological processes including cancer biology., Materials and Methods: We immunohistochemically examined the expression and distribution of Gremlin1 in non-neoplastic gastric mucosa in a series of 159 GC cases., Results: Among 159 GC primary tumors, 59 (37%) were positive for Gremlin1. Gremlin1-negative GC cases showed significantly more advanced clinicopathologic factors and a trend toward intestinal-type GC. Gremlin1 expression was also frequently observed in MUC5AC-positive and G-type GC cases. Gremlin1-negative GCs had a poorer survival rate than Gremlin1-positive GCs (p=0.002). Univariate and multivariate analyses revealed that Gremlin1 expression is an independent predictor of survival in GCs., Conclusion: These results indicate that Gremlin1 could be involved in GC progression and may be a good marker of long-term survival in GC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Transcribed ultraconserved regions (T-UCRs) are a novel class of noncoding RNAs that are highly conserved among the orthologous regions in most vertebrates. It has been reported that T-UCRs have distinct signatures in human cancers. We previously discovered the downregulation of T-UCR expression in gastric cancer (GC), indicating that T-UCRs could play an important role in GC biology. Uc.160+, a T-UCR reported to be downregulated in human cancer, has not been examined in GC., Methods: We analyzed the expression pattern of Uc.160+ in nonneoplastic and tumor tissues of the stomach by using uantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH), specifically focusing on the mechanism of transcriptional regulation and target genes that are regulated by T-UCRs. We also attempted to determine the effect of Uc.160+ expression on biological features of GC cell lines by Western blotting., Results: On the basis of the qRT-PCR and ISH results, Uc.160+ expression in adenoma and GC tissues was clearly downregulated compared with that in nonneoplastic mucosa tissues of the stomach. Cancer-specific DNA methylation in the promoter region of Uc.160 was observed by bisulfite genomic DNA sequencing analysis. The effect of DNA methylation on Uc.160+ expression was further confirmed by reporter gene assay. We also revealed that Uc.160+ inhibited the phosphorylation of Akt by regulating phosphatase and tensin homolog (PTEN) expression., Conclusions: These results indicate that Uc.160+ could possibly have a tumor suppressive role in GC.

Background: Some gastric adenomas may progress to adenocarcinoma in a short time, but others remain as adenoma for a long time., Methods: Among 1138 cases diagnosed as adenoma by biopsy at Kure Medical Association Hospital between 1990 and 2010, 51 adenomas were enrolled. Of these, 28 adenomas (group A) were followed for 60 months or longer with no progression to adenocarcinoma within 60 months, and the other 23 adenomas (group B) were upgraded to carcinoma by consecutive biopsies performed within 1 year after the first biopsy. These adenomas were compared clinicopathologically and immunohistochemically., Results: Macroscopically, the mean size of group B adenomas was significantly larger than that of group A adenomas (18.6 vs. 9.9 mm) at the first biopsy. The frequency of a depressed area in the adenoma was significantly higher in group B than group A. Microscopically none of group A but 7 (30.4%) of 23 group B adenomas showed severe atypia. Each of a highly proliferative gland measured by Ki-67 labeling, cellular atypical grade, gastric phenotype defined by MUC5AC and MUC6 and CD204-positive tumor-associated macrophage (TAM) was a significant risk factor for adenocarcinoma development in gastric adenoma by univariate analysis. Only moderate or severe atypia of adenoma cells and the TAM number in the stroma of adenomas were independent risk factors by multivariate analysis., Conclusions: As independent risk factors, cellular atypia may reconfirm the importance of morphological analysis, and the TAM number may indicate the significance of TAM function in gastric adenoma.

Docetaxel is the standard chemotherapy for metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients ultimately become refractory due to the development of docetaxel resistance. The transcribed ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs that are absolutely conserved across species and are involved in carcinogenesis including prostate cancer (PC). In this study, we investigated the transcriptional levels of 26 representative T-UCRs and determined the regions that were differentially expressed in PC. Quantitative real-time polymerase chain reaction analysis revealed that the expression of T-UCR Uc.63+ was increased in PC tissues. MTT assay and wound healing assay revealed that Uc.63+ was involved in cell growth and cell migration. miR-130b was predicted to have binding sites within the Uc.63+ sequence. The expression of miR-130b was significantly disturbed by the overexpression or knockdown of Uc.63+. We also showed that Uc.63+ regulated the expression of MMP2 via miR-130b regulation. Furthermore, overexpression of Uc.63+ increased the expression of AR and its downstream molecule PSA and promoted resistance to docetaxel through AR regulation. In patients treated with docetaxel, the expression of serum Uc.63+ in the docetaxel-resistant patients was higher than that in the docetaxel-sensitive patients ( P = 0.011). Moreover, Kaplan-Meier analysis showed that the high expression of serum Uc.63+ correlated with a worse prognosis ( P = 0.020). These results substantially support the important role that Uc.63+ plays in PC progression by interacting with miR-130b and indicate that Uc.63+ could potentially be a promising serum marker for deciding the best treatment for patients with CRPC., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Bladder cancer, the majority of which is urothelial carcinoma (UC), is a common malignancy worldwide. Genes encoding transmembrane/secretory proteins expressed specifically in certain cancers may be ideal biomarkers for cancer diagnosis and may represent therapeutic targets. In the present study, the expression and function of the bone marrow stromal cell antigen 2 (BST2) gene was analyzed in UC. Reverse transcription-quantitative polymerase chain reaction demonstrated that expression of BST2 in normal tissue samples was the highest in liver tissue. However, expression of BST2 in UC tissue samples was higher than in normal liver. Immunohistochemical analysis revealed weak or no staining of BST-2 in non-neoplastic mucosa, whereas UC tissue exhibited stronger and more extensive staining compared with non-neoplastic mucosa. BST-2 staining was observed mainly on UC cell membranes. In total, 28 (41%) of 69 UC cases were positive for BST-2. UC cases positive for BST-2 were more frequently T2/3/4 cases [so-called muscle-invasive bladder cancer (MIBC)] than Ta/is/1 cases (P=0.0001). However, Kaplan-Meier analysis demonstrated no association between BST-2 expression and survival. BST2 small interfering RNA (siRNA)-transfected T24 cells exhibited significantly reduced cell growth relative to negative control siRNA-transfected T24 cells. The levels of phosphorylated Akt and extracellular signal-regulated kinase were lower in BST2 siRNA-transfected T24 cells than in control cells. These results suggest the involvement of BST-2 in the pathogenesis of UC. Since BST-2 is expressed on the cell membrane, BST-2 may be a good therapeutic target for MIBC.

Background: Renal cell carcinoma (RCC) is one of the most common types of cancer in developed countries. Bone marrow stromal cell antigen 2 (BST2) gene, which encodes BST2 transmembrane glycoprotein, is overexpressed in several cancer types. In the present study, we analyzed the expression and function of BST2 in RCC., Materials and Methods: BST2 expression was analyzed by immunohistochemistry in 123 RCC cases. RNA interference was used to inhibit BST2 expression in a RCC cell line., Results: Immunohistochemical analysis showed that 32% of the 123 RCC cases were positive for BST2. BST2 expression was positively associated with tumour stage. Furthermore, BST2 expression was an independent predictor of survival in patients with RCC. BST2 siRNA-transfected Caki-1 cells displayed significantly reduced cell growth and invasive activity relative to negative control siRNA-transfected cells., Conclusion: These results suggest that BST2 plays an important role in the progression of RCC. Because BST2 is expressed on the cell membrane, BST2 is a good therapeutic target for RCC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The term "non-coding RNA" (ncRNA) is generally used to indicate RNA that does not encode a protein and includes several classes of RNAs, such as microRNA and long non-coding RNA. Several lines of evidence suggest that ncRNAs appear to be involved in a hidden layer of biological procedures that control various levels of gene expression in physiology and development including stem cell biology. Stem cells have recently constituted a revolution in regenerative medicine by providing the possibility of generating suitable cell types for therapeutic use. Here, we review the recent progress that has been made in elaborating the interaction between ncRNAs and tissue/cancer stem cells, discuss related technical and biological challenges, and highlight plausible solutions to surmount these difficulties. This review particularly emphasises the involvement of ncRNAs in stem cell biology and in vivo modulation to treat and cure specific pathological disorders especially in cancer. We believe that a better understanding of the molecular machinery of ncRNAs as related to pluripotency, cellular reprogramming, and lineage-specific differentiation is essential for progress of cancer therapy.