Growing evidence suggests that long non‐coding RNAs (lncRNAs) are associated with carcinogenesis. LncRNA small nucleolar RNA host gene 3 (SNHG3) is up‐regulated in various cancers and positively associated with poor prognosis of these cancers. However, the precise role of lncRNA SNHG3 in bladder cancer (Bca) remains unclear. In our research, we first reported that lncRNA SNHG3 was up‐regulated in bladder cancer tissues and positively related to poor clinical prognosis. Moreover, knockdown of lncRNA SNHG3 significantly suppressed the proliferation, migration, invasion and EMT process of Bca cells in vitro and vivo. Mechanistically, we revealed that suppression of SNHG3 evidently enhanced miR‐515‐5p expression and decreased GINS2 expression at posttranscriptional levels. Moreover, SNHG3 positively regulated GINS2 expression by sponging miR‐515‐5p under a competing endogenous RNA (ceRNA) mechanism. To sum up, our study suggested lncRNA SNHG3 acted as a microRNA sponge and an oncogenic role in the progression of bladder cancer.

Background: Bladder cancer (BLCA) is the most common genitourinary tumor but lacks specific diagnostic biomarkers. Recent years have witnessed significant advances in the use and approval of immune checkpoint blockade (ICB) therapy to manage BLCA at advanced stages when platinum-based therapy has failed. The tumor microenvironment (TME) is essential in impacting BLCA patients' prognosis and responsiveness to ICB therapy. CXCL12 is a stromal secreted factor that was essentially involved in regulating the TME among cancers. In this article, we thoroughly investigated the TME regulating roles of CXCL12 in BLCA and revealed its critical involvement in the development of BLCA, which was closely correlated with inflammatory fibroblasts (iCAFs). Methods: We examined the gene expression profiles in the TCGA and GEO database to reveal the potential association of CXCL12 with the carcinogenesis and prognosis of BLCA. The receiver operating characteristic curve was used to explore the accuracy of CXCL12 along with multiple iCAFs-associated genes in the diagnosis of BLCA. The MCP-COUNTER, ESTIMATE, and TIDE algorithms were applied to estimate the TME components and predict immunotherapy responsiveness. An iCAFs signature was constructed using the ssGSEA algorithm. The "maftool" R package analyzed the oncogenic mutations in BLCA patients. Bioinformatics analysis results were further validated through immunohistochemistry of clinical samples. IMvigor210 cohort was used to validate bioinformatic predictions of therapeutic responsiveness to immune checkpoint inhibitors. Results: This manuscript revealed a significantly reduced expression of CXCL12 in BLCA compared with normal tissue. The expressions of various marker genes for iCAFs were also reduced considerably in BLCA tissues, highlighting the reduction of iCAFs in the pathogenesis of BLCA. Further studies revealed that CXCL12 and iCAFs were associated with pathological features, TME remodeling and aging in BLCA patients. The iCAFs signature further confirmed the intricate immunomodulatory roles of iCAFs in BLCA. Gene mutation analysis revealed the essential relationship between iCAFs and the mutation frequency of oncogenic genes, including TP53 and FGFR3. Meantimes, iCAFs levels also significantly affected BLCA patients' mutations in the TP53 and RTK-RAS pathways. Finally, our results confirmed the significant exclusion of CD8 + T cells by iCAFs, which further influenced the immunotherapy responsiveness in BLCA patients. Conclusions: This article highlighted the impact of CXCL12 on the pathogenesis and progression of BLCA. The reduced expression levels of iCAFs markers, including CXCL12, were highly accurate in the diagnosis of BLCA, suggesting the reduction of iCAFs accompanied bladder carcinogenesis. However, both CXCL12 and iCAFs significantly impacted the prognosis and immunotherapy responsiveness for BLCA patients by remodeling the TME. Our results critically suggested the dual roles of iCAFs in the carcinogenesis and progression of BLCA. Further exploration of iCAFs might unravel potential diagnostic biomarkers and therapeutic targets for BLCA.

Bladder cancer (BLCA) is a tumor that possesses significant heterogeneity, and the tumor microenvironment (TME) plays an important role in the development of BLCA. The TME chiefly consists of tumor cells and tumor-infiltrating immune cells admixed with stromal components. Recent studies have revealed that stromal components, especially cancer-associated fibroblasts (CAFs), affect immune cell infiltration and modulate the extracellular matrix in the TME of BLCA, ultimately impacting the prognosis and therapeutic efficacy of BLCA. Among the subgroups of CAFs, myofibroblasts (myCAFs) were the most abundant and were demonstrated to play an essential role in affecting the prognosis of various tumors, including BLCA. However, the dynamic changes in myCAFs during carcinogenesis and tumor progression have been less discussed previously. With the help of bioinformatics algorithms, we discussed the roles of myCAFs in the carcinogenesis and prognosis of BLCA in this manuscript. Our study highlighted the pathogenesis of BLCA was accompanied by a decrease in the abundance of myCAFs, revealing potential protective properties of myCAFs in the carcinogenesis of BLCA. Meanwhile, the reduced expressions of myCAFs marker genes were highly accurate in predicting tumorigenesis. In contrast, we also demonstrated that myCAFs regulated extracellular matrix remodeling, tumor metabolism, cancer stemness, and oncological mutations, ultimately impacting the treatment responsiveness and prognosis of BLCA patients. Thus, our research revealed the bimodal roles of myCAFs in the development of BLCA, which may be associated with the temporal change of the TME. The in-depth study of myofibroblasts and the TME may provide potential diagnostic biomarkers and therapeutic targets for BLCA.