The role of cyclin-dependent kinase inhibitor 3 in the proliferation and migration of renal cell carcinoma.

The cyclin-dependent kinase inhibitor 3 (CDKN3) gene, is over expressed in renal cell carcinoma (RCC). However, the cell biology functions of RCC are not well understood. The present study aimed to verify the ability of CDKN3 to promote the proliferation and migration of RCC through in vitro experiments. Subsequently, the clinical prognostic effects were analyzed using The Cancer Genome Atlas (TCGA; https://www.cancer.gov/) and Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/). The chelators, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), an analogue of the anti-tumor agent, were screened through bioinformatics analysis. The expression of CDKN3 is positively correlated with the IC50 of Dp44mT. In two RCC cell lines, 786-0 and Caki-1, we conducted small interfering RNA (siRNA) knockdown of CDKN3 and overexpression of CDKN3 by transfection plasmid. Subsequently, we administered Dp44mT to examine the resulting alterations in cell proliferation, migration, and apoptosis, thereby elucidating the role of CDKN3 and Dp44mT in these processes. The results of the experiment revealed a positive association between CDKN3 expression and the proliferation of RCC cell lines. Down-regulating CDKN3 significantly increased the apoptosis rate and inhibited cell migration in 786-0 and Caki-1 cells. Furthermore, bioinformatics analysis revealed a high expression of CDKN3 in RCC and a negative association between CDKN3 expression and survival. Gene set enrichment analysis (GSEA) revealed a significant association between high CDKN3 expression and the cell cycle pathway. Furthermore, we identified Dp44mT as a drug highly correlated with CDKN3 through the database. Subsequent addition of Dp44mT resulted in similar findings to those observed upon CDKN3 knockdown. Our findings have important implications for the diagnosis and treatment of CDKN3 in RCC. Additionally, Dp44mT is likely to be a promising candidate for future clinical applications.

Epigenetic activation of METTL14 promotes docetaxel resistance in prostate cancer by promoting pri-microRNA-129 maturation.

The development of resistance to Docetaxel (DTX) compromises its therapeutic efficacy and worsens the prognosis of prostate cancer (PCa), while the underlying regulatory mechanism remains poorly understood. In this study, METTL14 was found to be upregulated in DTX-resistant PCa cells and PCa tissues exhibiting progressive disease during DTX therapy. Furthermore, overexpression of METTL14 promoted the development of resistance to DTX in both in vitro and in vivo. Interestingly, it was observed that the hypermethylation of the E2F1 targeting site within DTX-resistant PCa cells hindered the binding ability of E2F1 to the promoter region of METTL14, thereby augmenting its transcriptional activity. Consequently, this elevated expression level of METTL14 facilitated m6A-dependent processing of pri-miR-129 and subsequently led to an increase in miR-129-5p expression. Our study highlights the crucial role of the E2F1-METTL14-miR-129-5p axis in modulating DTX resistance in PCa, underscoring METTL14 as a promising therapeutic target for DTX-resistant PCa patients.

Silencing LINC00491 inhibits prostate cancer development through the miR-384/TRIM44 axis.

Accumulating evidence has demonstrated the key role of long noncoding (lnc)RNAs in tumorigenesis. Prostate cancer (PCa) is a cancer with high mortality that requires further exploration of the underlying molecular mechanisms. In the present study, we aimed to discover novel potential biomarkers for diagnosing PCa and targeting treatment. Overexpression of the lncRNA, LINC00491, was verified in PCa tumor tissues and cell lines using the real-time polymerase chain reaction. Cell proliferation and invasion were then analyzed via the Cell Counting Kit-8, colony formation, and transwell assays in vitro, and tumor growth in vivo. The interaction of miR-384 with LINC00491, as well as TRIM44, was investigated via bioinformatics analyses, subcellular fractionation, luciferase reporter gene assays, radioimmunoprecipitation, pull-down, and western blot analyses. LINC00491 was overexpressed in PCa tissues and cell lines. LINC00491 knockdown resulted in impaired cell proliferation and invasion in vitro and decreased tumor growth in vivo. Moreover, LINC00491 acted as a sponge for miR-384 and its downstream target, TRIM44. Additionally, miR-384 expression was downregulated in PCa tissues and cell lines, and its expression was negatively correlated with LINC00491. A miR-384 inhibitor restored the inhibitory effects of LINC00491 silencing on PCa cell proliferation and invasion. LINC00491 is a tumor promoter in PCa via enhancing TRIM44 expression by sponging miR-384 to facilitate the development of PCa. LINC00491 plays a significant role in PCa and could serve as both a biomarker for early diagnosis and a novel treatment target.

EXTL3 could serve as a potential biomarker of prognosis and immunotherapy for prostate cancer and its potential mechanisms.

BACKGROUND: Exostosin like glycosyltransferase 3 (EXTL3) had been reported to be associated with immune deficiency and play prognostic roles in various cancers. However, little is known about the associations between EXTL3 and prostate cancer (PCa). Hence, this article was designed to clarify their associations. METHODS: All original data were downloaded from The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) and CellMiner database was utilized, respectively, to identify EXTL3-related signaling pathways and drugs. We explored the relationships between EXTL3 expression and immunity to further evaluate the involvement of EXTL3 in response to immunotherapies. LncRNA/RBP/EXTL3 mRNA networks were also identified for its potential mechanism. RESULTS: Compared with normal prostate samples, EXTL3 was poorly expressed in PCa samples not only in mRNA expression levels, but also in protein expression levels, with worse overall survival (P < 0.05) and this gene could be an independent prognostic biomarker for PCa (both P < 0.05). EXTL3 was revealed to be markedly linked with seven signaling pathways in PCa by GSEA, including calcium, chemokine, ERBB, JAK STAT, MAPK, WNT, oxidative phosphorylation pathways. EXTL3 expression was also revealed to be significantly associated with MSI, immune cells, immune checkpoint molecules, tumor microenvironment and immune cells infiltration. We further predicted immune responses of EXTL3 gene to immunotherapies by TIDE database and the IMvigor210 cohort. A total of six LncRNA/RBP/EXTL3 mRNA networks were eventually identified for its potential mechanisms. CONCLUSIONS: EXTL3 could serve as a potential biomarker of prognosis and immunotherapy for PCa and six LncRNA/RBP/EXTL3 mRNA networks were also identified for its potential mechanisms.

MiR-129-5p promotes docetaxel resistance in prostate cancer by down-regulating CAMK2N1 expression.

This study focuses on the effect of miR-129-5p on docetaxel-resistant (DR) prostate cancer (PCa) cells invasion, migration and apoptosis. In our study, the expression of CAMK2N1 was assessed by qRT-PCR in PCa patient tissues and cell lines including PC-3 and PC-3-DR. Cells transfected with miR-129-5p mimics, inhibitor, CAMK2N1 or negative controls (NC) were used to interrogate their effects on DR cell invasions, migrations and apoptosis during docetaxel (DTX) treatments. The apoptosis rate of the PCa cells was validated by flow cytometry. Relationships between miR-129-5p and CAMK2N1 levels were identified by qRT-PCR and dual-luciferase reporter assay. CAMK2N1 was found to be down-expressed in DR PCa tissue sample, and low levels of CAMK2N1 were correlated with high docetaxel resistance and clinical prediction of poor survival. CAMK2N1 levels were decreased in DR PCa cells treated with DXT. We further explored that up-regulation of miR-129-5p could promote DR PCa cells viability, invasion and migration but demote apoptosis. Involved molecular mechanism studies revealed that miR-129-5p reduced downstream CAMK2N1 expression to further impact on chemoresistance to docetaxel of PCa cells, indicating its vital role in PCa docetaxel resistance. Our findings revealed that miR-129-5p contributed to the resistance of PC-3-DR cells to docetaxel through suppressing CAMK2N1 expression, and thus targeting miR-129-5p may provide a novel therapeutic approach in sensitizing PCa to future docetaxel treatment.

Assessing the Feasibility of Replacing Standard-Dose Bacillus Calmette-Guérin Immunotherapy with Other Intravesical Instillation Therapies in Bladder Cancer Patients: A Network Meta-Analysis.

BACKGROUND: Bacillus Calmette-Guérin (BCG) immunotherapy plays a key role in patients with bladder cancer. The shortage of intravesical BCG has motivated researchers to seek alternatives with equivalent efficacy If other alternative intravesical agents have equivalent efficacy compared to BCG, then it may be feasible to replace standard BCG with alternative options. METHODS: We searched all relevant evidence in multiple sources and key data was extracted from included studies. Conventional and network meta-analysis were conducted so that pooled odds ratios (ORs) for the event of tumor recurrence and progression can be computed. The relative efficacy of different intravesical instillation procedures was computed by pooled odds ratios and their 95% confidence or creditable intervals. Besides, several key model assumptions were evaluated in our analysis. RESULTS: Three intravesical instillation procedures have the potential for preventing tumor recurrence: standard-dose BCG (BCG_SD), Epirubicin (EPI) and Mitomycin C (MMC) (ORs < 1). Patients with BCG SD also exhibited a decreased risk of tumor recurrence and progression compared to those with EPI. No significant difference in the risk of tumor recurrence or progression was detected between patients treated with BCG_ SD and those with low-dose BCG (BCG_LD). Results of SUCRA indicated that BCG_EPI, BCG_ MMC and BCG SD had higher rankings with respect to tumor recurrence and progression. CONCLUSIONS: BCG SD, EPI and MMC exhibited established efficacy for preventing tumor recurrence in postoperative BC patients. The efficacy of BCG may not be significantly reduced if standard dose was reduced to a lower level. However, there is no consensus suggesting that intravesical BCG with standard dose can be replaced by alternating or sequentially combined intravesical instillation therapies.