Circ-SAR1A Promotes Renal Cell Carcinoma Progression Through miR-382/YBX1 Axis.

BACKGROUND: Accumulating evidence points to a role for circular RNAs (circRNAs) in important regulatory function in tumor advancement. We explored the effect and function of circ-SAR1A in renal cell carcinoma (RCC). METHODS: circ-SAR1A expression in RCC tissues and cell lines was explored by qRT-PCR. The roles of circ-SAR1A on RCC progression were explored by in vitro function assays. Moreover, we determined the underlying mechanism of circ-SAR1A in RCC progression through bioinformatics analysis and dual-luciferase reporter assays. RESULTS: Our data reveal that circ-SAR1A is significantly high in RCC tissues and cell lines. High circ-SAR1A levels are correlated to advanced Fuhrman grade, and lymph-node metastasis in RCC patients. Functional experiments indicate that circ-SAR1A suppression decreased RCC cell growth and invasion abilities in vitro. Mechanistically, circ-SAR1A upregulated YBX1 expression by sponging miR-382, resulting in promoting the growth and invasion in RCC cells. CONCLUSION: Our data indicate that the circ-SAR1A/miR-382/YBX1 axis plays a critical role in RCC progression, which serve as a potential novel treatment strategy of RCC.

LncRNA EMX2OS, Regulated by TCF12, Interacts with FUS to Regulate the Proliferation, Migration and Invasion of Prostate Cancer Cells Through the cGMP-PKG Signaling Pathway.

BACKGROUND: LncRNA EMX2OS (EMX2 opposite strand/antisense RNA) is notably downregulated in prostate cancer (PCa) tissues and may be regarded as a potential molecular biomarker for diagnosis and prognosis. However, its exact role in regulating the development of PCa is obscure. METHODS: The EMX2OS expression was assessed in PCa tissues, paracancer tissues, PCa cells and normal prostate epithelial cells by qPCR. Gain- and loss-of-function experiments were performed to investigate the role of EMX2OS and FUS in cGMP-PKG (cyclic guanosine monophosphate-dependent protein kinase)-mediated proliferation, invasion, and migration in human PCa cell lines DU145 and PC3. Then, the interaction of transcription factor 12 (TCF12) with EMX2OS promoter was confirmed by using the dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RNA binding protein immunoprecipitation and RNA pull-down assays were used to verify the interaction between EMX2OS and FUS protein. Finally, the role of EMX2OS and FUS in tumor growth in vivo was validated in a xenograft nude mouse model. RESULTS: TCF12 and EMX2OS were both downregulated in PCa tissues and cells, and they negatively regulated cell proliferation, migration and invasion, and activated cGMP-PKG pathway in DU145 and PC3 cells. TCF12 was a transcription factor of EMX2OS. TCF12 and EMX2OS overexpression both down-regulated cell proliferation, migration and invasion, and activated cGMP-PKG pathway in DU145 and PC3 cells. Furthermore, EMX2OS directly bound with FUS protein and had a synergy effect with FUS protein on cGMP-PKG-mediated cell functions, which could be suppressed by (D)-DT-2 (a cGMP-PKG inhibitor). In addition, the overexpression of FUS or EMX2OS individually markedly decreased the volume and weight of tumors in vivo, and co-overexpression of them further inhibited tumor growth. CONCLUSION: EMX2OS, transcriptionally regulated by TCF12, played a synergy role with FUS protein in regulating the proliferation, migration and invasion of PCa cells by activating the cGMP-PKG pathway.

MALAT1 silencing suppresses prostate cancer progression by upregulating miR-1 and downregulating KRAS.

BACKGROUND: Prostate cancer (PC) is the second leading cause of cancer-related deaths among men. Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) performed as an oncogene in multiple cancers including PC. However, the molecular mechanisms of MALAT1 implicated in PC progression have not been thoroughly elaborated. MATERIALS AND METHODS: Reverse transcription-quantitative polymerase chain reaction assay was used to detect the expressions of MALAT1 and microRNA-1 (miR-1). Protein levels of cleaved poly (ADP-ribose) polymerase, cleaved caspase-3, BAX, bcl-2, and KRAS were determined using a western blot assay. Cell proliferation was assessed by colony formation and MTS assays. Cell migration capacity was examined by transwell migration assay (Corning Incorporated, Corning, NY, USA). Apoptosis rate was measured by flow cytometry via double staining of annexin V-FITC and propidium iodide. Luciferase and RNA immunoprecipitation assays were employed to explore the relationship among miR-1, MALAT1, and KRAS. RESULTS: MALAT1 expression was upregulated and miR-1 expression was downregulated in PC tissues and cell lines. MALAT1 knockdown inhibited cell proliferation and migration, and promoted cell apoptosis in androgen receptor-negative DU145 and PC3 cells. Molecular mechanism explorations disclosed that MALAT1 acted as a molecular sponge of miR-1 in DU145 cells. Moreover, miR-1 downregulation partly abrogated MALAT1 silencing-mediated anti-proliferative, antimigratory, and proapoptotic effects in DU145 and PC3 cells. Further investigation revealed that KRAS was a target of miR-1 in DU145 cells. MALAT1 acted as a competing endogenous RNA of miR-1, resulting in the increase of KRAS expression in DU145 and PC3 cells. Furthermore, miR-1 overexpression hampered proliferation and migration and promoted apoptosis in DU145 and PC3 cells, while these effects were markedly weakened following KRAS upregulation. CONCLUSION: MALAT1 knockdown inhibited proliferation and migration and facilitated apoptosis by upregulating miR-1 and downregulating KRAS in androgen receptor-negative PCa cells, providing a new insight into the molecular basis of MALAT1 and a potential biomarker or therapeutic target for suppressing castration-resistant PC.

Posttranscriptional Regulation of Human Antigen R by miR-133b Enhances Docetaxel Cytotoxicity Through the Inhibition of ATP-Binding Cassette Subfamily G Member 2 in Prostate Cancer Cells.

Docetaxel (DTX)-based chemotherapy is a first-line therapy in patients with castration-resistant prostate cancer. However, development of DTX resistance remains a challenge in cancer treatment. miRNAs have been shown to be involved in drug resistance in tumors. Nevertheless, little is known about the function and detailed molecular mechanism of miR-133b in DTX resistance of prostate cancer cells. The current study showed that miR-133b was downregulated, while human antigen R (HuR) was upregulated in prostate cancer cells. HuR was identified as a target of miR-133b, and miR-133b could suppress HuR expression. Ectopic expression of miR-133b and HuR knockdown suppressed cell viability and promoted DTX-induced apoptosis in DTX-treated prostate cancer cells, which were restored by HuR overexpression. Furthermore, HuR overexpression partially abolished the inhibitory effect of miR-133b overexpression on ATP-binding cassette (ABC) subfamily G member 2 (ABCG2) expression in prostate cancer cells. ABCG2 overexpression relieved DTX and miR-133b cytotoxicity in prostate cancer cells. In conclusion, posttranscriptional regulation of HuR by miR-133b enhances DTX cytotoxicity through inhibition of ABCG2, revealing a novel miR-133b/HuR/ABCG2 regulatory pathway to overcome chemoresistance in prostate cancer cells.

Effects of exogenous hydrogen sulfide on the proliferation and invasion of human Bladder cancer cells.

OBJECTIVE: The objective of this study is to evaluate the effects of exogenous hydrogen sulfide (H2S) on the proliferation and invasion of human bladder cancer cells. METHODS: Human bladder cancer EJ cells were cultured and then treated with sodium bisulfide (NaHS) (100 µmol/L for low dosage, 200 µmol/L for moderate dosage, 400 µmol/L for high dosage). The differences on proliferation and invasion of EJ cells were detected among different groups with MTT and transwell invasion assays. The differences in the expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 among the groups were detected with Western blot. RESULTS: Cell proliferation activity was elevated by exogenous NaHS, with significantly statistical difference compared to the blank control group (P < 0.05). With the increased NaHS concentration, the EJ cell proliferation activity presented a statistically significant trend of increase, showing comparative differences among different groups (P < 0.05). Exogenous NaHS could also improve the invasion ability of bladder cancer EJ cells, which was significantly enhanced with increased NaHS dose (P < 0.001). The levels of MMP2 and MMP9 in EJ cells were significantly upregulated with the increased NaHS dose (P < 0.001). CONCLUSION: Exogenous H2S may promote cell proliferation and invasion by upregulating the expression level of MMP2 and MMP9 in human bladder cancer EJ cells.

Long non-coding RNA PCAT-1 contributes to tumorigenesis by regulating FSCN1 via miR-145-5p in prostate cancer.

Prostate cancer associated lncRNA transcript 1 (PCAT-1) has been identified as an oncogenic long non-coding RNA (lncRNA) in some solid tumors, including prostate cancer (PC). However, the molecular mechanism of PCAT-1 involved in PC is poorly defined. In this study, we found that PCAT-1 expression was up-regulated and miR-145-5p expression was down-regulated in PC tissues and cells. Function analysis indicated that PCAT-1 overexpression promoted proliferation, migration, invasion and inhibited apoptosis of PC cells. Rescue experiments demonstrated that miR-145-5p restoration attenuated the promotive effects of PCAT1 on PC progression, while Fascin-1 (FSCN1) upregulation relieved the anti-cancer role of miR-145-5p in PC. Mechanical analysis discovered that PCAT-1 could act as a miR-145-5p sponge to modulate FSCN1 expression. In conclusion, these findings suggested that PCAT-1 accelerated PC cell proliferation, migration, invasion and suppressed apoptosis by up-regulating FSCN1 mediated via miR-145-5p, hinting a potential therapeutic strategy for PC patients.

Downregulation of Rab23 in Prostate Cancer Inhibits Tumor Growth In Vitro and In Vivo.

Rab23, a novel member of the Rab GTPase family, was found to be implicated in the progression of some human cancers. However, what role Rab23 plays in prostate cancer (PCa) remains to be illustrated. In the present study, we investigated the expression pattern and roles of Rab23 in PCa. The study results showed that Rab23 was upregulated in PCa tissues and cell lines. Moreover, downregulation of Rab23 remarkably suppressed the proliferation, migration, and invasion of PCa cells. In addition, downregulation of Rab23 significantly downregulated the protein expression levels of Shh and Gli1. Furthermore, we found that the Gli1 inhibitor GANT-61 greatly enhanced the suppressive effect of Rab23 downregulation on PCa cells. In conclusion, we suggested Rab23 as a potential therapeutic target for PCa treatment.

Knockdown of FOXR2 suppresses the tumorigenesis, growth and metastasis of prostate cancer.

Fork-head box R2 (FOXR2), a member of FOX protein family, was reported to play important roles in the development and progression of cancers. However, the expression and function of FOXR2 in prostate cancer remain unclear. In this study, we investigated the role of FOXR2 in prostate cancer and cancer progression including the molecular mechanism that drives FOXR2-mediated oncogenesis. Our results showed that FOXR2 was overexpressed in prostate cancer cell lines. The in vitro experiments demonstrated that knockdown of FOXR2 significantly repressed the proliferation, migration and invasiveness of prostate cancer cells. Furthermore, the in vivo experiments indicated that knockdown of FOXR2 significantly attenuated prostate cancer growth. Finally, knockdown of FOXR2 significantly down-regulated the protein expression levels of ß-catenin, cyclinD1 and c-Myc in DU-145 cells. Taken together, our results demonstrated for the first time that FOXR2 plays a critical role in cell proliferation and invasion, at least in part, through inhibiting the Wnt/ß-catenin signaling pathway during prostate cancer progression. Thus, FOXR2 may be an attractive therapeutic target for the treatment of prostate cancer.

Tumor Protein D52 (TPD52) Inhibits Growth and Metastasis in Renal Cell Carcinoma Cells Through the PI3K/Akt Signaling Pathway.

Tumor protein D52 (TPD52) is a member of the TPD52-like protein family and plays different roles in various types of malignancies. However, its role in renal cell carcinoma (RCC) is still unclear. In this study, we investigated the role of TPD52 in RCC. The mechanism of TPD52 in RCC was also investigated. Our data demonstrated that the expression levels of TPD52 in both mRNA and protein were significantly decreased in RCC cells. Overexpression of TPD52 inhibited proliferation, migration, and invasion with decreased epithelial-mesenchymal transition (EMT) phenotype in RCC cells, as well as attenuated tumor growth in renal cancer xenografts. Mechanistically, overexpression of TPD52 significantly inhibited downregulated phosphorylation levels of PI3K and Akt in RCC cells. In conclusion, the present study demonstrated that TPD52 inhibited growth and metastasis of RCC, at least in part, by suppressing the PI3K/Akt signaling pathway. Therefore, these findings suggest that TPD52 may be a promising therapeutic target for the treatment of human RCC.

CYP17 T27C polymorphism and prostate cancer risk: a meta-analysis based on 31 studies.

OBJECTIVE: The cytochrome P450 17α-hydroxylase (CYP17) plays a vital role in androgen biosynthesis. A T-to-C polymorphism in the 5' promoter region of CYP17 has been implicated as a risk factor for prostate cancer, but the results of individual studies are inconclusive or controversial. To derive a more precise estimation of the relationship, we performed an updated meta-analysis from 31 studies based on 27 publications. METHODS: A comprehensive search was conducted to examine all the eligible studies of CYP17 polymorphism and prostate cancer risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. RESULTS: Overall, individuals with CC/CT genotype were not associated with prostate cancer risk (CC vs. TT: OR = 1.03, 95% CI = 0.86-1.24, P = 0.72, P heterogeneity < 0.0001; CT vs. TT: OR = 0.99, 95% CI = 0.87-1.12, P = 0.88, P heterogeneity = 0.0006). In the stratified analysis by ethnicity, there was a significantly increased risk of prostate cancer among individuals of African descent under the recessive model (OR = 1.56, 95% CI = 1.01-2.39, P = 0.04, P heterogeneity = 0.65). CONCLUSION: This meta-analysis suggested that CYP17 polymorphism might be associated with prostate cancer risk among individuals of African descent.

TGFbeta1 T29C polymorphism and cancer risk: a meta-analysis based on 40 case-control studies.

Transforming growth factor-beta1 (TGFbeta1) plays a significant role in regulating cellular proliferation and apoptosis. The TGFbeta1 T29C polymorphism reportedly affects cancer risk, but pertinent studies offer conflicting results. We therefore performed a meta-analysis based on 40 studies from 32 publications, assessing the strength of the association using odds ratios with 95% confidence intervals. Overall, no evidence has indicated that individuals carrying CC or CT genotypes had significantly increased cancer risks, compared with TT genotype carriers [CC vs. TT: odds ratio (OR)=1.10, 95% confidence interval (95% CI)=1.00-1.21, P=0.06; CT vs. TT: OR=1.07, 95% CI=0.99-1.16, P=0.09). However, stratified analysis by cancer type and ethnicity indicated a significantly increased risk of prostate cancer (CT vs. TT: OR=1.28, 95% CI=1.01-1.61, P=0.04) and cancer in those of Asian descent (CC vs. TT: OR=1.26, 95% CI=1.03-1.53, P=0.02; CT vs. TT: OR=1.20, 95% CI=1.01-1.43, P=0.04). This association was also observed in the dominant model for prostate cancer. Although not all bias could be eliminated, this meta-analysis suggested that TGFbeta1 29C was a low-penetrant risk factor for prostate cancer and cancer in Asians. A larger single study is still required to evaluate any association with other types of cancer or in other populations.