Regulation of antitumor miR‐144‐5p targets oncogenes: Direct regulation of syndecan‐3 and its clinical significance

In the human genome, miR‐451a , miR‐144‐5p (passenger strand), and miR‐144‐3p (guide strand) reside in clustered microRNA (mi RNA ) sequences located within the 17q11.2 region. Low expression of these mi RNA s is significantly associated with poor prognosis of patients with renal cell carcinoma ( RCC ) ( miR‐451a : P = .00305; miR‐144‐5p: P = .00128; miR‐144‐3p : P = 9.45 × 10 −5 ). We previously reported that miR‐451a acted as an antitumor mi RNA in RCC cells. Involvement of the passenger strand of the miR‐144 duplex in the pathogenesis of RCC is not well understood. Functional assays showed that miR‐144‐5p and miR‐144‐3p significantly reduced cancer cell migration and invasive abilities, suggesting these mi RNA s acted as antitumor mi RNA s in RCC cells. Analyses of miR‐144‐5p targets identified a total of 65 putative oncogenic targets in RCC cells. Among them, high expression levels of 9 genes ( FAM 64A , F2 , TRIP 13 , ANKRD 36 , CENPF , NCAPG , CLEC 2D , SDC 3 , and SEMA 4B ) were significantly associated with poor prognosis ( P < .001). Among these targets, expression of SDC 3 was directly controlled by miR‐144‐5p , and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC 3 regulation. Data showed that expression of 10 of the downstream genes ( IL 18 RAP , SDC 3 , SH 2D1A , GZMH , KIF 21B , TMC 8 , GAB 3 , HLA ‐ DPB 2 , PLEK , and C1 QB ) significantly predicted poor prognosis of the patients ( P = .0064). These data indicated that the antitumor miR‐144‐5p /oncogenic SDC 3 axis was deeply involved in RCC pathogenesis. Clustered mi RNA s ( miR‐451a , miR‐144‐5p , and miR‐144‐3p ) acted as antitumor mi RNA s, and their targets were intimately involved in RCC pathogenesis.