Changcheng Guo

The increasing incidence and mortality of prostate cancer worldwide significantly impact the life span of male patients, emphasizing the urgency of understanding its pathogenic mechanism and associated molecular changes that regulate tumor progression for effective prevention and treatment. RNA modification, an important post-transcriptional regulatory process, profoundly influences tumor cell growth and metabolism, shaping cell fate. Over 170 RNA modification methods are known, with prominent research focusing on N6-methyladenosine, N7-methylguanosine, N1-methyladenosine, 5-methylcytidine, pseudouridine, and N4-acetylcytidine modifications. These alterations intricately regulate coding and non-coding RNA post-transcriptionally, affecting the stability of RNA and protein expression levels. This article delves into the latest advancements and challenges associated with various RNA modifications in prostate cancer tumor cells, tumor microenvironment, and core signaling molecule androgen receptors. It aims to provide new research targets and avenues for molecular diagnosis, treatment strategies, and improvement of the prognosis in prostate cancer.

Docetaxel is the preferred chemotherapeutic agent in patients with castrate‐resistant prostate cancer (CRPC). However, patients eventually develop docetaxel resistance and in the absence of effective treatment options. Consequently, it is essential to investigate the mechanisms generating docetaxel resistance and develop novel alternative therapeutic targets. RNA sequencing was undertaken on docetaxel‐sensitive and docetaxel‐resistant prostate cancer (PCa) cells. Subsequently, chemoresistance, cancer stemness, and lipid metabolism were investigated. To obtain insight into the precise activities and action mechanisms of NOTCH3 in docetaxel‐resistant PCa, immunoprecipitation, mass spectrometry, ChIP, luciferase reporter assay, cell metabolism, and animal experiments were performed. Through RNA sequencing analysis, we found that NOTCH3 expression was markedly higher in docetaxel‐resistant cells relative to parental cells, and that this trend was continued in docetaxel‐resistant PCa tissues. Experiments in vitro and in vivo revealed that NOTCH3 enhanced stemness, lipid metabolism, and docetaxel resistance in PCa. Mechanistically, NOTCH3 is bound to TUBB3 and activates the MAPK signaling pathway. Moreover, NOTCH3 was directly regulated by MEF2A in docetaxel‐resistant cells. Notably, targeting NOTCH3 and the MEF2A/TUBB3 signaling axis was related to docetaxel chemoresistance in PCa. Overall, these results demonstrated that NOTCH3 fostered stemness, lipid metabolism, and docetaxel resistance in PCa via the TUBB3 and MAPK signaling pathways. Therefore, NOTCH3 may be employed as a prognostic biomarker in PCa patients. NOTCH3 could be a therapeutic target for PCa patients, particularly those who have developed docetaxel resistance.

Surgical manipulation has a risk of triggering the shedding of circulating tumor cells (CTCs) in patients with malignancies, However, perioperative change of circulating tumor cells in cytoreductive radical prostatectomy (CRP) for patients with oligometastatic hormone-sensitive prostate cancer (omHSPC) has not yet been well documented. This study aimed to assess whether CRP is a safe procedure for patients with omHSPC by monitoring the perioperative change of CTCs and investigating its impact on long-term oncologic outcomes. We have observed a significant decrease between the median CTC counts before and after surgery (6 vs. 4, p = 0.026). Comparing preoperative and postoperative CTC levels, seven patients increased (CTC increase group), one did not change and nineteen decreased (CTC non-increase group). PSA response rates in CTC increase group were lower than those in CTC non-increase group (73.0% vs 99.8%, p = 0.162), and nadir PSA was higher in CTC increase group (0.043 vs 0.003, p = 0.072). The CTC increase was positively correlated with the nadir PSA (r = 0.386, p = 0.047). The median follow-up period was 71.6 months, we found that there was no significant difference in clinical-pathological, operative variables or long-term oncologic outcomes between perioperative CTC increase and non-increase groups. In the entire cohort, the CTC level significantly decreased after surgery. There was no significant differences in long-term oncologic outcomes between the CTC increase and non-increase groups, implying that CRP potentially represents a safe procedure for the treatment of patients with omHSPC. The results need to be confirmed in a prospective large-scale clinical trial.

Early studies indicated that the androgen-deprivation-therapy with antiandrogen Enzalutamide could increase prostate cancer patients’ survival by an average of 4.8 months. Yet Enz might also have some adverse effects via increasing the PCa cell invasion. Here we found Enz treatment could increase oncogene SALL4 expression to increase the cancer stem cells population that resulted in increasing the PCa cell invasion. Mechanisn dissection revealed that Enz could function via androgen receptor to transcriptionally regulate the SALL4 expression via direct binding to the androgen-response-elements on the SALL4 5'-promoter. The consequences of such Enz/AR/SALL4 axis may then lead to transcriptionally increase the SOX2-OCT4 expression to increase the CSC population to increase the PCa cell invasion. Together, results from multiple in vitro cell lines and in vivo mouse model all conclude that Enz may induce the adverse effect of increasing PCa cell invasion via altering the AR/SALL4/SOX2-OCT4 signaling to increase the CSC population, and targeting this newly identified signaling with small molecule of sh-SALL4 may decrease this adverse effect to further suppress the PCa progression.

The aim of the present study was to investigate the expression of spalt like transcription factor 4 (SALL4) in the three most common types of renal cell carcinomas (RCC) [clear cell RCC (ccRCC), papillary renal cell carcinoma (pRCC) and chromophobe RCC (chRCC)], and the association with the overall survival (OS) of patients. The Cancer Genome Atlas (TCGA) database and RCC samples were used to investigate the expression levels of the SALL4 gene and its association with the OS in the three types of RCC based on the analysis of the transcriptome, copy number and survival data. It was found that SALL4 was highly expressed in ccRCC and pRCC tumor tissue, and low mRNA expression level of SALL4 indicated a prolonged survival in both ccRCC and pRCC. This mRNA expression level was associated with pathological Tumor‑Node‑Metastasis stage, M and T stages in both ccRCC and pRCC. The analysis of the enriched pathway results suggested that SALL4 may act via translation initiation, and that the related genes promoted the progression of RCC. Moreover, the high expression level of SALL4 was detected in RCC samples and serum from patients. It was demonstrated that SALL4 promotes increased viability in RCC cells. Therefore, the present results suggest that SALL4 may be a sensitive and specific cancer biomarker in ccRCC and pRCC. Furthermore, targeting of SALL4 may improve RCC therapy and prolong the survival of patients with ccRCC or pRCC.

The objective of the present study was to assess the expression of CD105 and its association with overall survival in three subtypes of renal cell carcinoma (RCC), namely clear cell (cc)RCC, papillary (p)RCC and chromophobe (ch)RCC. Data regarding the transcriptome and copy number of genes in RCC tumor samples and survival were obtained from The Cancer Genome Atlas. Bioinformatics analysis revealed that CD105 is overexpressed in ccRCC tumor tissue vs. normal renal tissue, and a higher CD105 copy number in ccRCC tissues was significantly associated with longer patient survival. The effect of the mRNA expression of CD105 in all three types of RCC and the copy number in pRCC and chRCC on patient survival was insignificant, but certain trends were observed. In addition, CD105 mRNA expression was associated with the metastasis and tumor stage, as well as pathological stage in ccRCC and pRCC. Pathway enrichment analysis revealed that CD105 may, through translation initiation of associated genes, promote RCC progression. The results of the present study suggest that in RCC tumors, the association of CD105 with different stages is complex. To evaluate the role of CD105 in RCC, its function should be assessed in addition to its expression. The exact influence of CD105 mRNA expression and copy number in RCC tumors on patient survival and the underlying mechanisms require further elucidation.

Transforming growth factor-β1 (TGF-β1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-β1 in bladder cancer cells and the relationship with POK erythroid myeloid ontogenic factor (Pokemon). TGF-β1 and its receptors mediate several tumorigenic cascades that regulate cell proliferation, migration, and survival of bladder cancer cells. Bladder cancer cells T24 were treated with different levels of TGF-β1. Levels of Pokemon, E-cadherin, Snail, MMP2, MMP9, Twist, VEGF, and β-catenin messenger RNA (mRNA) and protein were examined by real-time quantitative fluorescent PCR and Western blot analysis, respectively. The effects of TGF-β1 on epithelial–mesenchymal transition of T24 cells were evaluated with wound-healing assay, proliferation of T24 was evaluated with reference to growth curves with MTT assay, and cell invasive ability was investigated by Transwell assay. Data show that Pokemon was inhibited by TGF-β1 treatment; the gene and protein of E-cadherin and β-catenin expression level showed decreased markedly after TGF-β1 treatment (P < 0.05). While the bladder cancer cell after TGF-β1 treatment showed a significantly reduced wound-closing efficiency at 6, 12, and 24 h, mechanistic analyses demonstrated that different levels of TGF-β1 promotes tumor cell growth, migration, and invasion in bladder cancer cells (P < 0.01, P < 0.05, respectively). In summary, our findings suggest that TGF-β1 may inhibit the expression of Pokemon, β-catenin, and E-cadherin. The high expression of TGF-β1 leads to an increase in the phenotype and apical-base polarity of epithelial cells. These changes of cells may result in the recurrence and progression of bladder cancer at last. Related mechanism is worthy of further investigation.

The expression patterns of the Dickkopf (Dkk) family of proteins varies in different cancers. In the present study, the expression levels of Dkk1 and Dkk3 were investigated in clear cell renal cell carcinoma (ccRCC) tissues. Dkk1 and Dkk3 serum levels were also examined in patients with ccRCC, and the association between clinicopathological features and Dkk levels was investigated. Serum Dkk1 and Dkk3 were quantified using ELISA in 64 patients with ccRCC and in 30 healthy individuals (controls). The expression levels of Dkk1 and Dkk3 were analyzed in tumor and adjacent normal tissues obtained from patients with ccRCC (n=20) using quantitative polymerase chain reaction (qPCR), western blot analysis and immunohistochemistry. The mean serum levels of Dkk1 and Dkk3 in the patients with ccRCC were significantly lower than those in the healthy controls. Furthermore, the serum Dkk1 levels were significantly lower at higher tumor‑node‑metastasis stages and tumor grades. qPCR, western blot analysis and immunohistochemistry revealed a significant decrease in the Dkk1 and Dkk3 mRNA and protein levels in the tumor tissues compared with the adjacent normal tissues. Consequently, Dkk1 and Dkk3 may present a novel molecular target for the diagnosis and therapeutic treatment of ccRCC.