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The mechanisms underlying the effects of cancer-associated fibroblasts (CAFs) on cancer stemness and tumor progression in renal cell carcinoma (RCC) have not been elucidated yet. In the present study, we found that the enrichment of CAFs was positively associated with tumor progression and cancer stemness in RCC. Further investigation revealed that CAFs could enhance cancer stemness through delivering exosomes to RCC cells, and miR-181d-5p was identified as the critical exosomal miRNA in CAF secreted exosomes by small RNA sequencing and subsequent screening assays. Mechanistically, exosomal miR-181d-5p transferred from CAFs to RCC cells directly suppressed the expression of ring finger protein 43 (RNF43) and activated Wnt/β-catenin signaling pathway, thus promoted cancer stemness and tumor progression. Overexpression of RNF43 strongly suppressed stemness properties and the effects could be reverted by miR-181d-5p. Overall, our findings revealed a crucial mechanism by which CAFs secreted exosomal miRNAs to enhance cancer stemness and thus promote RCC progression, suggesting a new avenue based on CAF secreted miRNAs for more effective targeted therapies.

Background Emerging evidence suggests that LMNB1 is involved in the development of multiple cancer types. However, there is no study reporting the potential role of LMNB1 in a systematic pan-cancer manner. Methods The gene expression level and potential oncogenic roles of LMNB1 in The Cancer Genome Atlas (TCGA) database were analyzed with Tumor Immune Estimation Resource version 2 (TIMER2.0), Gene Expression Profiling Interactive Analysis version 2 (GEPIA2), UALCAN and Sangerbox tools. Pathway enrichment analysis was carried out to explore the possible mechanism of LMNB1 on tumorigenesis and tumor progression. The therapeutic effects of LMNB1 knockdown combined with PARP inhibition on human cancers were further investigated in vitro. Results LMNB1 upregulation is generally observed in the tumor tissues of most TCGA cancer types, and is verified in kidney renal clear cell carcinoma using clinical specimens of our institute. High level of LMNB1 expression usually predicts poor overall survival and disease free survival for patients with tumors. Mechanically, LMNB1 level is positively correlated with CD4+ Th2 cell infiltration and DNA homologous recombination repair gene expression. In vitro experiments reveal that targeting LMNB1 has a synergistic effect on prostate cancer with PARP inhibitor treatment. Conclusions LMNB1 is a biomarker of CD4+ Th2 cell infiltration and DNA homologous recombination repair in human cancers. Blockage of LMNB1 combined with PARP inhibitor treatment could be a promising therapeutic strategy for patients with cancers.

Background Previous studies have demonstrated that transcription factor SOX9 which was reactivated in prostate cancer (Pca) and promoted tumor growth was a poor prognostic biomarker for Pca. Nevertheless, the regulatory mechanism underlying SOX9 upregulation in Pca still remains unclear. Several cytokines widely distributed in the tumor microenvironment (TME) have been reported to be involved in the regulation of SOX9, suggesting that cancer-associated fibroblasts (CAFs), one of the main sources of secreted factors in TME, may play a role in regulating SOX9 expression. Methods Herein, an in vitro model of paracrine interaction between primary CAFs and Pca cells (both AR-positive and AR-negative Pca cells), was applied to investigate the molecular mechanism of SOX9 upregulation during Pca progression. The regulatory axis was validated by in vivo experiments and The Cancer Genome Atlas (TCGA) data. Results Conditional medium from Pca CAFs (CAF-CM) upregulated the expression of SOX9, which was also proved to be essential for CAF-induced tumor progression. Further analysis showed that it was hepatocyte growth factor (HGF) secreted by CAFs that was responsible for the SOX9 elevation in Pca cells via activating c-Met signaling. Mechanistically, HGF/c-Met signaling specifically activated MEK1/2-ERK1/2 pathway which then induced phosphorylated status and protein upregulation of FRA1. Furthermore, ChIP assay demonstrated that FRA1 transcriptionally upregulated SOX9 expression by binding to the TPA-responsive element (TRE) sequence in the promoter of SOX9 gene. We also found that HGF/c-Met-ERK1/2-FRA1-SOX9 axis was relatively conserved in human and mouse species by validating in mouse Pca cells (RM-1). Conclusions Our results revealed a novel insight into the molecular mechanism that SOX9 expression in Pca cells is promoted by CAFs, through the HGF/cMet-ERK1/2-FRA1 axis. Besides, SOX9 may serve as an alternative marker for the activated HGF/c-Met signaling to enroll the optimal Pca patients for HGF/c-Met inhibition treatment, since it is much more stable and easier to detect.