Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with poor survival outcomes. In addition, oxysterol-binding protein-like (OSBPL) family members are reported to be involved in lipid binding and transport and play critical roles in tumorigenesis. However, relationships between PDAC and OSBPL family members have not comprehensively been elucidated. In this study, we used the Oncomine and GEPIA 2 databases to analyze OSBPL transcription expressions in PDAC. The Kaplan–Meier plotter and TIMER 2.0 were used to assess the relationships between overall survival (OS) and immune-infiltration with OSBPL family members. Co-expression data from cBioPortal were downloaded to assess the correlated pathways with OSBPL gene family members using DAVID. The expressions of OSBPL3, OSBPL8, OSBPL10, and OSBPL11 were found to be highly upregulated in PDAC. Low expressions of OSBPL3, OSBPL8, and OSBPL10 indicated longer OS. The functions of OSBPL family members were mainly associated with several potential signaling pathways in cancer cells, including ATP binding, integrin binding, receptor binding, and the renin-angiotensin system (RAS) signaling pathway. The transcription levels of OSBPL gene family members were connected with several immune infiltrates. Collectively, OSBPL family members are influential biomarkers for the early diagnosis of PDAC and have prognostic value, with the promise of precise treatment of PDAC in the future.

Colorectal cancer (CRC) is a heterogeneous disease with changes in the genetic and epigenetic levels of various genes. The molecular assessment of CRC is gaining increasing attention, and furthermore, there is an increase in biomarker use for disease prognostication. Therefore, the identification of different gene biomarkers through messenger RNA (mRNA) abundance levels may be useful for capturing the complex effects of CRC. In this study, we demonstrate that the high mRNA levels of 10 upregulated genes (DPEP1, KRT80, FABP6, NKD2, FOXQ1, CEMIP, ETV4, TESC, FUT1, and GAS2) are observed in CRC cell lines and public CRC datasets. Moreover, we find that a high mRNA expression of DPEP1, NKD2, CEMIP, ETV4, TESC, or FUT1 is significantly correlated with a worse prognosis in CRC patients. Further investigation reveals that CTNNB1 is the key factor in the interaction of the canonical Wnt signaling pathway with 10 upregulated CRC-associated genes. In particular, we identify NKD2, FOXQ1, and CEMIP as three CTNNB1-regulated genes. Moreover, individual inhibition of the expression of three CTNNB1-regulated genes can cause the growth inhibition of CRC cells. This study reveals efficient biomarkers for the prognosis of CRC and provides a new molecular interaction network for CRC.

The impact of chemotherapy-induced tumor cell pyroptosis on fibroblasts, a key stromal cell type within the tumor microenvironment (TME), remains unexplored. Here, we report morphologically and molecularly distinct subtypes of cancer-associated fibroblasts (CAFs) in bladder cancer, including αSMA ⁺ IL-6 ⁻ myofibroblastic CAFs (myCAFs), αSMA ⁻ IL-6 ⁺ inflammatory CAFs (iCAFs), and hybrid i/myCAFs. Caspase-1–dependent tumor pyroptosis releases several inflammatory chemokines, converting αSMA ⁺ CAF into iCAFs in a CCR6-dependent manner. This is clinically relevant, as a fibroblast gene signature driven by iCAF markers and collagen type III is enriched in patients with chemoresistant bladder cancer after neoadjuvant chemotherapy. Contrary to the current notion, iCAFs, rather than myCAFs, produce collagen III in response to chemotherapy, supporting the expansion of cancer stem cells (CSCs). Thus, tumor cell pyroptosis initiates an iCAF-CSC feedforward loop that drives chemoresistance, indicating that inflammatory cell death is not universally beneficial to anticancer therapy, depending on the target cell type.

Bladder cancer progression is closely linked to metabolic changes within the tumor microenvironment (TME), particularly elevated lactate levels. Lipocalin 2 (LCN2), a protein involved in iron regulation, has been implicated in tumor progression in several cancers, but its regulatory mechanisms and role in bladder cancer remain unclear. Bladder cancer cell lines were treated with exogenous lactate or subjected to inhibition of endogenous lactate production to evaluate changes in LCN2 expression. The role of Signal Transducer and Activator of Transcription 3 (STAT3) was assessed using genetic knockdown and pharmacological inhibitors. Functional assays including migration, epithelial-to-mesenchymal transition (EMT), sphere formation, and stemness marker analysis were performed to determine the biological effects of LCN2. Chemoresistance to gemcitabine was examined with and without LCN2 silencing. Clinically, LCN2 expression was significantly associated with the pathological relevance of bladder tumors. Lactate significantly induced LCN2 expression in bladder cancer cells through activation of STAT3. Disruption of STAT3 signaling reduced LCN2 levels. High LCN2 expression correlated with advanced tumor grade, poor prognosis, and shorter overall survival. Functionally, LCN2 promoted EMT, enhanced cell migration, and increased stem cell-like properties, as evidenced by elevated stemness markers and sphere-forming ability. Moreover, lactate-induced LCN2 expression conferred resistance to gemcitabine treatment, while LCN2 knockdown restored chemosensitivity. This study identifies tumor-derived lactate as a key inducer of LCN2 expression via STAT3 activation in bladder cancer. LCN2 contributes to tumor aggressiveness, cancer stemness, and chemoresistance. Targeting the STAT3-LCN2 signaling axis may offer a promising therapeutic strategy to suppress bladder cancer progression and overcome treatment resistance within a lactate-rich TME.

Esophageal squamous cell carcinoma (ESCC) is a common and fatal malignancy with an increasing incidence worldwide. Over the past decade, concurrent chemoradiotherapy (CCRT) with or without surgery is an emerging therapeutic approach for locally advanced ESCC. Unfortunately, many patients exhibit poor response or develop acquired resistance to CCRT. Once resistance occurs, the overall survival rate drops down rapidly and without proper further treatment options, poses a critical clinical challenge for ESCC therapy. Here, we utilized lab-created CCRT-resistant cells as a preclinical study model to investigate the association of chemoradioresistantresistance with miRNA-mediated cell plasticity alteration, and to determine whether reversing EMT status can re-sensitize refractory cancer cells to CCRT response. During the CCRT treatment course, refractory cancer cells adopted the conversion of epithelial to mesenchymal phenotype; additionally, miR-200 family members were found significantly down-regulated in CCRT resistance cells by miRNA microarray screening. Down-regulated miR-200 family in CCRT resistance cells suppressed E-cadherin expression through snail and slug, and accompany with an increase in N-cadherin. Rescuing expressions of miR-200 family members in CCRT resistance cells, particularly in miR-200b and miR-200c, could convert cells to epithelial phenotype by increasing E-cadherin expression and sensitize cells to CCRT treatment. Conversely, the suppression of miR-200b and miR-200c in ESCC cells attenuated E-cadherin, and that converted cells to mesenchymal type by elevating N-cadherin expression, and impaired cell sensitivity to CCRT treatment. Moreover, the results of ESCC specimens staining established the clinical relevance that higher N-cadherin expression levels associate with the poor CCRT response outcome in ESCC patients. Conclusively, miR-200b and miR-200c can modulate the conversion of epithelial–mesenchymal phenotype in ESCC, and thereby altering the response of cells to CCRT treatment. Targeting epithelial–mesenchymal conversion in acquired CCRT resistance may be a potential therapeutic option for ESCC patients.