Abstract
Targeted therapy is a standard of care for metastatic renal cell carcinoma (RCC) but the response rate is not overwhelmed, which only prolongs a short survival of patients due to the onset of therapeutic resistance. Although the mechanisms are not fully understood, the presence of cancer initiating cells (CIC) may underlie the drug resistance. Nevertheless, identifying CIC phenotypes with its biomarkers in RCC appear to be diverse and controversial from many reports. In this study, we took a different approach to focus on the regulatory mechanism in RCC-CIC and unveil DAB2IP-mediated miR-138 expression that plays a critical role in modulating stem-like phenotypes in RCC via targeting the ABC transporter (ABCA13) as well as oncogenic histone methyltransferase EZH2 while down regulation of miR-138 gene expression in RCC is due to epigenetic gene silencing by DNA methyltransferase 1 (DNMT1). We also characterize the individual mechanism by which ABCA13 in RCC-CIC contributes to its drug resistance and. EZH2 maintain stem-like phenotypes. Noticeably, elevated expression of ABCA13 and EZH2 is correlated with overall survival of RCC patients, which can be used as potential prognostic markers. Taken together, this study demonstrates a potent and unique pathway of DAB2IP-mediated miR-138 in modulating CIC phenotypes during RCC progression and also offers a new therapeutic strategy of targeting drug resistant RCC.
Highlights
The incidence of renal cell carcinoma (RCC) has been steadily rising over the past years [1]
We took a different approach to focus on the regulatory mechanism in RCC-cancer initiating cells (CIC) and unveil DAB2IP-mediated miR-138 expression that plays a critical role in modulating stem-like phenotypes in RCC via targeting the ATPbinding cassette (ABC) transporter (ABCA13) as well as oncogenic histone methyltransferase EZH2 while down regulation of miR-138 gene expression in RCC is due to epigenetic gene silencing by DNA methyltransferase 1 (DNMT1)
We further demonstrated that the activities of ABCA13 and EZH2 3′-untranslated region (3′-UTR) reporters were significantly higher in KD cells than in Con cells and the presence of miR-138 could suppress the activities of 3′-UTR reporters of these genes (Figure 5D and 5E), which corresponded to the protein expression of ABCA13 or EZH2 (Figure 5F and 5G) respectively
Summary
The incidence of renal cell carcinoma (RCC) has been steadily rising over the past years [1]. RCC is by far the most lethal urologic malignancy because it’s metastatic disease due to the resistance to chemotherapy, targeted therapy and radiation, and is largely incurable with a 5-year survival rate of less than 10%. In spite of recent advancements and clear clinical benefits observed with firstline targeted agents in RCC in terms of improved survival, a subset of patients do not appear to experience clinical benefit from targeted therapy and eventually acquired drug resistance. Cancer stem cell (CSC) model provides additional mechanism of drug resistance. CSC is considered as a cancer initiating cell (CIC) with poorly differentiated, immortal, self-renewal capabilities that can give rise to numerous progeny cells [5]
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