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

Abstract

In the human genome, miR‐451a, miR‐144‐5p (passenger strand), and miR‐144‐3p (guide strand) reside in clustered microRNA (miRNA) sequences located within the 17q11.2 region. Low expression of these miRNAs 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 miRNA 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 miRNAs acted as antitumor miRNAs 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 (FAM64A, F2,TRIP13,ANKRD36,CENPF,NCAPG,CLEC2D,SDC3, and SEMA4B) were significantly associated with poor prognosis (P < .001). Among these targets, expression of SDC3 was directly controlled by miR‐144‐5p, and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC3 regulation. Data showed that expression of 10 of the downstream genes (IL18RAP,SDC3,SH2D1A,GZMH,KIF21B,TMC8,GAB3,HLA‐DPB2,PLEK, and C1QB) significantly predicted poor prognosis of the patients (P = .0064). These data indicated that the antitumor miR‐144‐5p/oncogenic SDC3 axis was deeply involved in RCC pathogenesis. Clustered miRNAs (miR‐451a, miR‐144‐5p, and miR‐144‐3p) acted as antitumor miRNAs, and their targets were intimately involved in RCC pathogenesis.

Involvement of dual‐strand of the miR‐144 duplex and their targets in the pathogenesis of lung squamous cell carcinoma

“…In contrast to miR‐144‐3p analyses, few reports have examined the functional significance of miR‐144‐5p in cancer cells. Analyses of miRNA signatures by RNA sequencing showed that both strands of miR‐144‐5p and miR‐144‐3p were frequently downregulated in several cancers . In our studies, we focused on both strands of the miR‐144 duplex and investigated the antitumor functions and targets of the duplex in cancer cells .…”

“…This study is the third paper reporting the antitumor functions of both strands of the miR‐144 duplex in cancer cells. Importantly, low expression of miR‐144‐5p and miR‐144‐3p significantly predicted short survival in patients with RCC . Moreover, high expression of the oncogenic genes controlled by these miRNAs also predicted short survival in patients with RCC, suggesting that the miR‐144 duplex and its targets were deeply involved in RCC pathogenesis …”

“…Moreover, detailed analyses of our original miRNA expression signatures by RNA sequencing have revealed that passenger strands of miRNAs actually act as antitumor miRNAs and are involved in cancer pathogenesis . Additionally, our recent studies showed that both strands of the miR‐144 duplex (ie, the passenger strand miR‐144‐5p and the guide strand miR‐144‐3p ) are downregulated in bladder cancer and RCC tissues and act as antitumor miRNAs . The involvement of both strands of the miRNA duplex in cancer pathogenesis is a new concept for cancer research.…”

Prognostic value of Kinesin‐4 family genes mRNA expression in early‐stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy

“…KIF4A could enhance cell proliferation, promote tumor metastasis, predict patient prognosis and act as the potential therapeutic target in cancer treatment for breast cancer, lung cancer, colorectal cancer, and hepatocellular carcinoma . Researchers had reported that KIF21B as a downstream target gene regulated by the miR‐144‐5p/syndecan‐3 axis which participated in the pathogenesis of renal cell carcinoma and its expression could predict the patient prognosis outcome . Agnelli et al reconstructed the gene regulatory networks in multiple myeloma and revealed that KIF21B with a prognostic importance could predict the survival of patients .…”

“…Meanwhile, its expression level affected the axonal transport and nervous system development in patients with Down syndrome . Finally, it was important to note that the expression of KIF21B could predict the prognosis of patients with renal cell carcinoma and multiple myeloma …”