The impact of obesity and sexual behavior on prostate cancer risk is mediated by testosterone levels: a mendelian randomization study and mediation analysis.

Background: The relationship between obesity, sexual behavior, and prostate cancer (PCa) has been widely debated, contributing to a lack of understanding of its potential mechanisms and hindering the development of effective prevention measures. Purpose: The aim of this study was to examine the causal effect of body mass index (BMI), age at first sexual intercourse (AFS), and bioavailable testosterone levels on PCa while also quantifying the potential roles of mediators. Method: We conducted a Mendelian randomization (MR) study using summary statistics from genome-wide associations of BMI (152,893 European males), AFS (182,791 European males), bioavailable testosterone (184,205 European males), and PCa (79,148 cases, 61,106 controls, European ancestry). Inverse-variance weighted method, weighted median method, MR-Egger regression, Least Absolute Shrinkage and Selection Operator (LASSO), and outlier test were used for MR analyses. Reverse MR and mediation analysis were performed. Data analyses were conducted from December 2022 to July 2023. Results: The results showed that genetic liability to BMI was protective of PCa (OR, 0.82; 95% CI: 0.74-0.91; P = 3.29 × 10-4). Genetic liability to later AFS (OR, 1.28; 95% CI: 1.08-1.53; P = 5.64 × 10-3) and higher bioavailable testosterone levels (OR = 1.11, 95% CI: 1.01-1.24, P = 0.04) were associated with an increased risk of PCa. All of these potential causal effects could only be forwarded and were not affected by prostate specific antigen (PSA) screening. After controlling for bioavailable testosterone levels, the causal impact of BMI and AFS on PCa was no longer significant. The mediation analysis suggested that the causal influence of AFS/BMI on PCa relied on bioavailable testosterone levels. Conclusion: In conclusion, the difference between the univariable and multivariable MR results suggested that the causal influence of BMI and AFS on PCa relied on bioavailable testosterone levels. Further work is needed to identify other risk factors and to elucidate the specific mechanisms that underlie this causal pathway.

MicroRNA-142-3p promotes renal cell carcinoma progression by targeting RhoBTB3 to regulate HIF-1 signaling and GGT/GSH pathways.

MicroRNAs play a critical regulatory role in different cancers, but their functions in renal cell carcinoma (RCC) have not been elucidated. Reportedly, miR-142-3p is involved in the tumorigenesis and the development of RCC in vitro and is clinically correlated with the poor prognosis of RCC patients. However, the molecular target of miR-142-3p and the underlying mechanism are unclear. In this study, we found that miR-142-3p was upregulated in RCC tumor tissues and downregulated in exosomes compared to normal tissues. The expression of miR-142-3p was inversely associated with the survival of patients with kidney renal clear cell carcinoma (KIRC). RhoBTB3 was reduced in RCC, and miR-142-3p plays an inverse function with RhoBTB3 in KIRC. The direct interaction between RhoBTB3 and miR-142-3p was demonstrated by a dual luciferase reporter assay. miR-142-3p promoted metastasis in the xenograft model, and the suppression of miR-142-3p upregulated RhoBTB3 protein expression and inhibited the mRNAs and proteins of HIF1A, VEGFA, and GGT1. Also, the miR-142-3p overexpression upregulated the mRNA of HIF1A, VEGFA, and GGT1. In conclusion, miR-142-3p functions as an oncogene in RCC, especially in KIRC, by targeting RhoBTB3 to regulate HIF-1 signaling and GGT/GSH pathways, which needs further exploration.

NEAT1 variant 1 weakens the genome-wide effect of miR-3122 on blocking H3K79me3 in bladder cancer.

Nuclear-enriched abundant transcript 1 (NEAT1) is one of the most well-studied long non-coding RNAs (lncRNAs) in multiple human carcinoma. Two distinct variants of NEAT1, however, are never illuminated their specific functions and mechanisms underlying carcinogenesis. In this study, biotin-labelled NEAT1 variants were generated to incubate with cell lysate of bladder cancer cell T24 cells, and fished a batch of RNA substances. Here, we observed that NEAT1.1 (the short transcript) could capture 122 microRNAs (miRNAs), 36 small nucleolar RNAs (snoRNAs), 55 lncRNAs and 38 mRNAs while NEAT1.2 (the long transcript) could obtain 142 miRNAs, 51 snoRNAs, 72 lncRNAs and 41 mRNAs. Furthermore, we also found that the distinctions of RNA binding substances between these two variants were mainly expressed in nucleus rather than cytoplasm. GO analysis indicated that these non-coding RNAs governed histone modification, nucleosome assembly and chromosome organization. We picked up miRNA miR-3122, which substantially interacted with NEAT1.1, and found that histone H3K79me3 was reduced in bladder cancer T24, BIU-87 and EJ-1 cells after miR-3122 overexpression, and rescued by NEAT1.1 additional compensation. Nonetheless, we failed to find that miR-3122 could interfere with expression of H3K79 methyltransferase disruptor of telomeric silencing-1 like (DOT1L). Interestingly, we harvested histone 3 fished by biotin-labelled miR-3122, and validated this intercrossing using RNA immunoprecipitation. Taken together, we demonstrated that NEAT1.1 weakened the effect of miR-3122 on H3K79me3 suppression in bladder cancer.

miR-499a inhibits the proliferation and apoptosis of prostate cancer via targeting UBE2V2.

BACKGROUND: Prostate cancer is one of the malignant tumors of the urinary system and ranks second among the fatal cancers in men. And with age, the incidence of prostate cancer will increase linearly. METHODS: In this study, we measured the expression of Ubiquitin Conjugating Enzyme E2 V2 (UBE2V2) in prostate cancer tissues and cell lines by WB and explored the effect of UBE2V2 on the proliferation characteristics of prostate cancer by MTT and colony formation test. RESULTS: In our research, we found that the UBE2V2 protein level in prostate cancer cell lines was significantly higher than the UBE2V2 protein level in normal prostate cells, and the mRNA expression level did not change significantly compared with normal prostate tissue cells. At the same time, we found that miR-499a combined with UBE2V2 inhibited the expression of UBE2V2 in prostate cancer cells. CONCLUSIONS: In conclusion, our results indicate that miR-499a inhibits the proliferation of human prostate cancer cells by targeting UBE2V2, which will provide a potential target for the treatment of prostate cancer.

Potent antitumor efficacy of interleukin-18 delivered by conditionally replicative adenovirus vector in renal cell carcinoma-bearing nude mice via inhibition of angiogenesis.

It has been demonstrated that interleukin 18 (IL-18) exerts antitumor activity. In this study, we investigated whether oncolytic adenovirus-mediated gene transfer of IL-18 could induce strong antitumor activity. A tumor-selective replicating adenovirus expressing IL-18 (ZD55-IL-18) was constructed by insertion of an IL-18 expression cassette into the ZD55 vector, which is based on deletion of the adenoviral E1B 55-kDa gene. ZD55-IL-18 could express substantially more IL-18 than Ad-IL-18 because of replication of the vector. It has been shown that ZD55-IL-18 exerted a strong cytopathic effect and significant apoptosis in renal cell carcinoma. ZD55-IL-18 significantly decreased VEGF and CD34 expression in the tumor cells. Treatment of established tumors with ZD55-IL-18 showed much stronger antitumor activity than that induced by ZD55-EGFP or Ad-IL-18. These data indicated that oncolytic adenovirus expressing IL-18 could exert potential antitumor activity via inhibition of angiogenesis and offer a novel approach to cancer therapy.

Inhibition of renal cancer cell growth by oncolytic adenovirus armed short hairpin RNA targeting hTERT gene.

RNA interference (RNAi) has been proved to be a powerful tool for gene knockdown purpose and holds a great promise for the treatment of cancer. Our previous study demonstrated that the reduction of hTERT expression by means of chemically synthesized siRNAs and shRNAs expressed from plasmid resulted in proliferation inhibition in human renal carcinoma cells. In this study, we constructed a novel oncolytic adenovirus-based shRNA expression system, ZD55-hTERT, and to explore ZD55-hTERT-mediated RNAi for hTERT gene silencing. Our results showed that ZD55-hTERT could induce silencing of hTERT gene effectively, allow for efficient tumor-specific viral replication and induce the apoptosis of tumor cells effectively in vitro and in nude mice. We conclude that combining shRNA gene therapy and oncolytic virotherapy can enhance antitumor efficacy as a result of synergism between CRAd oncolysis and shRNA antitumor responses.