Abstract
BackgroundDysfunctional transcription machinery with associated dysregulated transcription characterizes many malignancies. Components of the mediator complex, a principal modulator of transcription, are increasingly implicated in cancer. The mediator complex subunit 10 (MED10), a vital kinase module of the mediator, plays a critical role in bladder physiology and pathology. However, its role in the oncogenicity, metastasis, and disease recurrence in bladder cancer (BLCA) remains unclear.ObjectiveThus, we investigated the role of dysregulated or aberrantly expressed MED10 in the enhanced onco-aggression, disease progression, and recurrence of bladder urothelial carcinoma (UC), as well as the underlying molecular mechanism.MethodsUsing an array of multi-omics big data analyses of clinicopathological data, in vitro expression profiling and functional assays, and immunocytochemical staining, we assessed the probable roles of MED10 in the progression and prognosis of BLCA/UC.ResultsOur bioinformatics-aided gene expression profiling showed that MED10 is aberrantly expressed in patients with BLCA, is associated with high-grade disease, is positively correlated with tumor stage, and confers significant survival disadvantage. Reanalyzing the TCGA BLCA cohort (n = 454), we showed that aberrantly expressed MED10 expression is associated with metastatic and recurrent disease, disease progression, immune suppression, and therapy failure. Interestingly, we demonstrated that MED10 interacts with and is co-expressed with the microRNA, hsa-miR-590, and that CRISPR-mediated knockout of MED10 elicits the downregulation of miR-590 preferentially in metastatic UC cells, compared to their primary tumor peers. More so, silencing MED10 in SW1738 and JMSU1 UC cell lines significantly attenuates their cell proliferation, migration, invasion, clonogenicity, and tumorsphere formation (primary and secondary), with the associated downregulation of BCL-xL, MKI67, VIM, SNAI1, OCT4, and LIN28A but upregulated BAX protein expression. In addition, we showed that high MED10 expression is a non-inferior biomarker of urothelial recurrence compared with markers of cancer stemness; however, MED10 is a better biomarker of local recurrence than any of the stemness markers.ConclusionThese data provide preclinical evidence that dysregulated MED10/MIR590 signaling drives onco-aggression, disease progression, and recurrence of bladder UC and that this oncogenic signal is therapeutically actionable for repressing the metastatic/recurrent phenotypes, enhancing therapy response, and shutting down stemness-driven disease progression and relapse in patients with BLCA/UC.
Highlights
Bladder cancer (BLCA), with 573,278 new cases in 2020 and a projected 72.9% increase in incidence by 2040, ranks as one of the most diagnosed malignancies and a leading cause of cancerassociated mortality for both sexes and all ages, globally [1]
This was corroborated by Cox PH modeling-based volcano plot visualization of differentially expressed genes in the TCGA BLCA cohort (n = 412), showing that the overexpression of the med10 gene was associated with increased hazard ratio (3.53-fold, p < 0.001) (Figure 1B)
Survival analyses of the TCGA BLCA cohort showed that compared with their high mediator complex subunit 10 (MED10) counterparts (n = 333), patients with low MED10 expression (n = 56) enjoyed an 18% to 27% survival advantage from days 1,000 to 5,000 (concordance index = 48.67; hazard ratio HR = 1.78, p = 0.028) (Figure 1C)
Summary
Bladder cancer (BLCA), with 573,278 new cases in 2020 and a projected 72.9% increase in incidence by 2040, ranks as one of the most diagnosed malignancies and a leading cause of cancerassociated mortality for both sexes and all ages, globally [1]. There is accruing evidence of the exploitable role of circulating tumor cells (CTCs) as biomarkers of diagnosis and prognosticators of disease recurrence, progression, and poor survival in patients with BLCA/UC [9]. The high incidence of recurrent NMIBC and poor survival rate of MIBC, despite these advances in diagnostic [8, 9] and therapeutic strategies [6, 7], necessitate the discovery and characterization of novel actionable molecular targets and development of new therapeutic approaches. Its role in the oncogenicity, metastasis, and disease recurrence in bladder cancer (BLCA) remains unclear
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