MicroRNA-143 Targets MACC1 to Inhibit Cell Invasion and Migration in Colorectal cancer

Abstract

BackgroundMicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on anti-metastasis strategy. Metastasis-associated in colon cancer-1 (MACC1) has been newly identified to express highly in colorectal cancer (CRC) and promote tumor metastasis through transactivating metastasis-inducing HGF/MET signaling pathway. In this study, we investigated whether miRNA 143 is involved in the regulation of MACC1 and thus plays a functional role in CRC.ResultsUsing both in silico prediction and western blot assay, we found the previously reported tumor suppressive miR-143 targeted MACC1 in CRC. The direct interaction between them was confirmed by 3' UTR luciferase reporter gene. In concordance with the inhibitory effects induced by siRNA mediated knockdown of MACC1, restoration of miR-143 by mimics in SW620 cells significantly attenuated cell growth, migration and invasion. It is notable that combined treatment of miR-143 mimics and MACC1 siRNA induced synergistic inhibitory effects compared to either miR-143 mimics or MACC1 siRNA treatment alone. Conversely, reduction of miR-143 by inhibitors in SW480 cells apparently stimulated these phenotypes. Furthermore, we observed that miR-143 level was inversely correlated with MACC1 mRNA expression in CRC tissues.ConclusionsOur findings newly described miR-143/MACC1 link and provided a potential mechanism for MACC1 dysregulation and contribution to CRC cell invasion. It may help to estimate the therapeutic utility of miR-143 in CRC.

MicroRNA-143 inhibits tumorigenesis in hepatocellular carcinoma by downregulating GATA6

“…Numerous reports have identified significantly reduced miR-143 expression in various tumors such as non-small cell lung, colorectal, gastric, pancreatic and prostate cancers, osteosarcomas, cervical cancer and leukemia (9)(10)(11)(12)(13)(14)(15)(16). However, to our knowledge, the current study is the first to investigate the function of miR-143 in regulating human HCC.…”

Investigation of MACC1-AS1 gene mutations in colorectal cancer

“…MACC1, miRNA-143'ün hedefidir, yüksek miRNA-143 ifadesi belirgin bir şekilde MACC1 protein ifadesini azaltır (8). KRK yayılımında, miRNA-143'ün, MACC1 genini hedefleyerek KRK hücre yayılımı ve göçünü baskıladığı bulunmuştur (8).…”

“…Hücre çoğalması, hareketlilik, nüfus edebilirlik ve yayılımı sağlamak için epitelyal-mezenkimal geçişte önemli bir rol oynar (5,7). MACC1 proteini bir transkripsiyon faktörü olarak işlev görür ve reseptör tirozin kinazların (Met) özendirici bölgelerine (promoter) bağlanır (5)(6)(7)(8). Met'in transkripsiyon etkinliğini uyarmak için esas olan, Met özendirici bölgesi üzerinde özel Sp1 bağlanma bölgelerinin 60 bç yakınına bağlanır ve HGF/c-Met uyarı yolağının etkinliğini uyarır ve hücre çoğalmasını, hareketliliğini ve yayılımı arttırır (9).…”

“…Klinik çalışmalar MACC1'in uzak yayılımcı gelişim için tanı koydurucu bir belirteç ve yüksek yayılım riskli kolorektal kanser belirlenmesine olanak olduğunu düşündürmektedir (10). Çünkü MACC1, birincil kolon kanserine göre yayılımcı kolon kanserinde aşırı ifade olur (5,6,(8)(9)(10). Benzer şekilde, normal dokulara göre birincil kolon kanserinde de aşırı ifade olur (9,11).…”

MCP-1-induced protein-1, an immune regulator

“…miR-155 promotes the immune response by down-regulating the expression levels of its targets, including SHIP1 and SOCS1, whereas miR146aand miR-21 attenuate the immune response (O′Connell et al, 2012). miR-143 targets hexokinase 2 to regulate cancer cell glycolysis, and also MACC1 to regulate cell invasion and migration Zhang et al, 2012). The regulation of these miRNA expression levels by MCPIP1 may be important for immune response, particularly for cancers.…”