Background: There is no good prognostic model that could predict the prognosis of bladder cancer (BCa) and the benefit of immunotherapy.Methods: Through the least absolute shrinkage and selection operator (LASSO) algorithm, we constructed a 13‐mRNA immune signature from the TCGA cohort (n = 406). We validated its prognostic value and predictive value for the benefit of immunotherapy with four independent validation cohort (GSE13507 [n = 256], GSE31684 [n = 93], GSE32894 [n = 308], and IMvigor210 cohort [n = 298]).Results: Our results indicating that high‐risk group with higher inhibitory immune cell infiltration (regulatory T cells [Tregs] and macrophage, etc), higher expression of immune checkpoints, and more T cell suppressive pathways (transforming growth factor β [TGF‐β], epithelial‐mesenchymal transition [EMT], etc) were activated. Besides, the immune signature showed a good predictive value for the benefit of immunotherapy in a cohort of urothelial carcinoma patients treated with PD‐L1.Conclusions: The immune signature constructed is convenient to classify the immunotherapeutic susceptibility of patients with BCa, so as to achieve precision immunotherapy for BCa.

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that is both common and aggressive, with a rising incidence in recent decades. Hypoxia is a key factor that plays a vital role in the tumorigenesis and metastasis of malignancy. However, the precise mechanisms of hypoxia driving ccRCC progression were not totally uncovered. Our study found that hypoxia level was elevated in ccRCC and might be an independent risk factor of prognosis in ccRCC patients. We identified a key protein PLOD2 was induced under hypoxic conditions and strongly associated with poor prognosis in ccRCC patients. When PLOD2 was depleted, the proliferation and migration of ccRCC cells were reduced in vitro and in vivo, while overexpression of PLOD2 had the opposite effect. Mechanically, the study further revealed that PLOD2 was transcriptionally activated by HIF1A, which binds to a specific promoter region of the PLOD2 gene. PLOD2 was also shown to interact with EGFR, leading to the phosphorylation of the receptor. Furthermore, PLOD2 was responsible for binding to the extracellular domain of EGFR, which ultimately activated the AKT signaling pathway, thus promoting the malignant progression of ccRCC. Treatment with the PLOD2 inhibitor Minoxidil significantly suppressed ccRCC progression by inactivating the EGFR/AKT signaling axis. In summary, the findings of this study shed light on the molecular mechanisms behind PLOD2 expression in ccRCC and suggest that it may serve as a potential predictor and therapeutic target for the clinical prognosis and treatment of ccRCC.

SCL/TAL1 interrupting locus (STIL) regulates centriole replication and causes chromosome instability, which is closely related to malignant tumors. The purpose of our study was to investigate the role of STIL in bladder cancer (BC) tumorigenesis for the first time. The public database indicated that STIL is highly expressed and correlated with the cell cycle in BC. Immunohistochemistry staining showed that STIL expression is significantly elevated in BC tissues compared with paracancer tissues. CRISPR-Cas9 gene editing technology was used to induce BC cells to express STIL-specific sgRNA, revealing a significantly delayed growth rate in STIL knockout BC cells. Moreover, cell cycle arrest in the G0/G1 phase was triggered by decreasing STIL, which led to delayed BC cell growth in vitro and in vivo. Mechanically, STIL knockout inhibited the PI3K/AKT/mTOR pathway and down-regulated the expression of c-myc. Furthermore, SC79 (AKT activating agent) partially reversed the inhibitory effects of STIL knockout on the proliferation and migration of BC cells. In conclusion, STIL enhanced the PI3K/AKT/mTOR pathway, resulting in increased expression of c-myc, ultimately promoting BC occurrence and progression. These results indicate that STIL might be a potential target for BC patients.

Synthetic immunosuppressive glucocorticoids (GCs) are widely used to control inflammatory bowel disease (IBD). However, the impact of GC signaling on intestinal tumorigenesis remains controversial. Here, we report that intestinal epithelial GC receptor (GR), but not whole intestinal tissue GR, promoted chronic intestinal inflammation-associated colorectal cancer in both humans and mice. In patients with colorectal cancer, GR was enriched in intestinal epithelial cells and high epithelial cell GR levels were associated with poor prognosis. Consistently, intestinal epithelium–specific deletion of GR (GR iKO) in mice increased macrophage infiltration, improved tissue recovery, and enhanced antitumor response in a chronic inflammation–associated colorectal cancer model. Consequently, GR iKO mice developed fewer and less advanced tumors than control mice. Furthermore, oral GC administration in the early phase of tissue injury delayed recovery and accelerated the formation of aggressive colorectal cancers. Our study reveals that intestinal epithelial GR signaling repressed acute colitis but promoted chronic inflammation–associated colorectal cancer. Our study suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that, although synthetic GC treatment for IBD should be used with caution, there is a therapeutic window for GC therapy during colorectal cancer development in immunocompetent patients.

The progression and outcome of bladder cancer (BLCA) are critically affected by the propensity of tumor metastasis. Our previous study revealed that activation of the mevalonate (MVA) pathway promoted migration of BLCA cells; however, the exact mechanism is unclear. Here we show that elevated expression of MVA pathway enzymes in BLCA cells, correlating with poorer patient prognosis by analyzing single-cell and bulk-transcriptomic datasets. Inhibition of the MVA pathway, either through knockdown of farnesyl diphosphate synthase (FDPS) or using inhibitors such as zoledronic acid or simvastatin, led to a marked reduction in BLCA cell migration. Notably, this effect was reversed by administering geranylgeranyl pyrophosphate (GGPP), not farnesyl pyrophosphate (FPP) or cholesterol, indicating the specificity of geranylgeranylation for cell motility. Moreover, we found that RhoB, a Rho GTPase family member, was identified as a key effector of the impact of the MVA pathway on BLCA metastasis. The post-translational modification of RhoB by GGPP-mediated geranylgeranylation influenced its protein stability through the ubiquitin-proteasome pathway. Additionally, overexpression of RhoB was found to block the membrane translocation of integrin β1 in BLCA cells. In summary, our findings underscore the role of the MVA pathway in BLCA metastasis, providing insights into potential therapeutic targets of this malignancy.

RNA-binding proteins (RBPs) are pivotal mediators of the alternative splicing (AS) machinery of pre-mRNA. Research has demonstrated that the AS process is significantly dysregulated and plays a crucial role in bladder cancer (BLCA). We conducted comprehensive screening and analysis of the TCGA-BLCA cohort, specifically focusing on genes with significant differences in expression levels between carcinoma and adjacent non-cancerous tissues. Among the 500 differentially expressed genes, 5 RNA-binding proteins were identified. Only the RNA-binding protein with multiple splicing (RBPMS) demonstrated a consistent downregulation in BLCA and was correlated with an unfavorable prognosis for affected patients. Subsequent experiments revealed that RBPMS exerted inhibitory effects on the epithelial-mesenchymal transition (EMT) pathway and the migratory potential of BLCA cells. RNA-Seq analysis identified ANKRD10 as a key target mRNA regulated by RBPMS in BLCA. RBPMS depletion in BLCA cells resulted in AS of ANKRD10 and increased ANKRD10-2 expression. ANKRD10-2 functioned as a transcriptional co-activator of MYC proteins, thereby augmenting their transcriptional activity. Furthermore, ANKRD10-2 knockdown significantly rescued the migration enhancement induced by RBPMS depletion in BLCA cells. Taken together, this study revealed a mechanism whereby RBPMS suppresses the migration and invasion of BLCA cells by attenuating MYC pathway activity via the AS of ANKRD10.