Dicer suppresses the malignant phenotype in VHL-deficient clear cell renal cell carcinoma by inhibiting HIF-2α

Abstract

Both the von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) pathway and microRNA (miRNA) regulation are important mechanisms underlying the development and progression of clear cell renal cell carcinoma (ccRCC). Here we demonstrate that VHL deficiency leads to downregulation of Dicer and, in turn, defects in the miRNA biogenesis machinery in ccRCCs. Dicer inhibited expression of HIF-2α, which was a direct target of Dicer-dependent miR-182-5p in VHL-deficient ccRCCs. Ectopic Dicer expression in VHL-deficient ccRCCs suppressed tumor growth and angiogenesis by inhibiting HIF-2α both in vitro and in vivo. Reduced Dicer mRNA levels served as an independent prognostic factor for poor survival in patients with VHL-deficient ccRCC. Our results indicate that downregulation of Dicer in VHL-deficient ccRCCs contributes to high levels of HIF-2α and a malignant phenotype, which suggests Dicer could be a useful therapeutic target for managing this disease.

Dysregulation of the miRNA biogenesis components DICER1, DROSHA, DGCR8 and AGO2 in clear cell renal cell carcinoma in both a Korean cohort and the cancer genome atlas kidney clear cell carcinoma cohort

“…Dysregulation of miRNA biogenesis components has been reported to be associated with carcinogenesis (18), cancer chemosensitivity (19), angiogenesis (13), metastasis (20), proliferation and migration (21), and the prognosis of patients with cancer (20,22) in various cancers, including ccRCC (12,13).…”

“…Although the dysregulation and pathophysiological role of DICER1 in ccRCC has been investigated (12,13), studies of other miRNA biogenesis components, such as DROSHA, DGCR8, and AGO2 are needed. In the present study, we investigated the mRNA levels of miRNA biogenesis components and analyzed their clinicopathological relevance in the TCGA KIRC cohort and a Korean ccRCC cohort.…”

“…Accumulating evidence reveals that dysregulated miRNA biogenesis components have pathophysiological importance in various human cancers (7)(8)(9)(10)(11). Furthermore, Dicer has been reported to be down-regulated in and to suppress the malignant phenotype of ccRCC (12,13). Interestingly, significant associations were observed between haplotypes/diplotypes of the DROSHA SNPs (rs6877842 and rs10719) and ccRCC recurrence (14).…”

ROLE OF COMPONENTS OF microRNA MACHINERY IN CARCINOGENESIS

“…Moreover, low expression of Dicer befits to be a significant prognostic factor for cervical malignancy and other tumor types [34]. Previous studies have shown that inhibition of Dicer in von Hippel -Lindau deficient clear cell renal cell carcinoma contributed to the high levels of the hypoxia-inducible factors-2α and a cancer phenotype, which suggests Dicer could be a useful therapeutic target for managing this disease [35]. miR-200a and miR-31 are targeted for Dicer and are involved in the carcinogenesis, cell migration, and behavior of castration-resistant prostate cancer, showing that they could be possible biomarkers for monitoring of prostate cancer progression [36].…”

Discerning functional hierarchies of microRNAs in pulmonary hypertension

“…Additional complexity likely exists, as more recent studies have suggested. For instance, hypoxia decreases Dicer expression, which in turn reduces the overall biogenesis of miRNAs (49)(50)(51). In some cases, this process may be promoted by direct miRNA engagement of Dicer (52).…”