Abstract
microRNA (miRNA) dysregulation is frequently observed in colon cancer. Previous studies found that miR-223 is upregulated in colon cancer and functions as an oncogene. Conversely, p120 is often downregulated or even absent in colon cancer, and is a likely tumor suppressor. The present study showed that increased miR-223 and decreased p120 levels are associated with colon cancer malignancy, and p120 expression is negatively correlated with miR-223 expression. A dual luciferase reporter assay showed that miR-223 directly targets p120. miR-223 upregulation in a colon cancer cell line upregulated c-Myc, cyclinD1, MMP7, and vimentin expression, downregulated E-cadherin, increased nuclear expression of β-catenin, and enhanced RhoA activation. We suggest miR-223 may promote colon cancer cell invasion and metastasis by downregulating p120, thereby reducing intercellular adhesion, promoting RhoA activity, and activating β-catenin signaling. Thus miR-223 functions as an oncogene in colon cancer and may be a potential diagnostic and therapeutic target for anti-colon cancer treatment.
Highlights
Colon cancer is the third most common and deadly malignant tumor type in both men and women [1]
Adhesion junctions (AJs) are important for maintaining intercellular adhesion, and include the E-cadherin (E-cad)/p120 catenin (p120)/β-catenin/αcatenin complex. p120 released from AJs reduces intercellular adhesion through E-cad degradation and promotes cell migration by regulating Rho GTP activity [4,5,6]. p120 is a member of the catenin family that binds the highly conserved E-cad juxtamembrane domain, stabilizing E-cad at the membrane, and regulating E-cad endocytosis. p120 is reportedly downregulated or translocated in a variety of human tumors and is often associated with poor prognosis [7,8,9,10,11,12]. p120 gene mutations are rare, suggesting that other mechanisms, such as transcriptional downregulation, epigenetic modification, or microRNA-mediated gene silencing, may downregulate p120 in tumors [13]
Many microRNAs reportedly play roles in tumor development [14]. miRNAs are a class of small, non-coding RNAs approximately 18–25 nucleotides in length that post-transcriptionally regulate mRNA. miRNAs can directly combine with the target mRNA 3’ untranslated region (3’-UTR), inhibiting target mRNA translation or promoting its degradation [15]. miR-223 expression is increased in colon cancer patient serum and tumor tissues [16, 17], and is associated with malignant www.impactjournals.com/oncotarget tumor behavior and poor prognosis [18, 19]
Summary
Colon cancer is the third most common and deadly malignant tumor type in both men and women [1]. P120 released from AJs reduces intercellular adhesion through E-cad degradation and promotes cell migration by regulating Rho GTP activity [4,5,6]. Many microRNAs (miRNAs) reportedly play roles in tumor development [14]. MiR-223 expression is increased in colon cancer patient serum and tumor tissues [16, 17], and is associated with malignant www.impactjournals.com/oncotarget tumor behavior and poor prognosis [18, 19]. The present study confirmed that p120 is a miR-223 target gene, and assessed miR-223 tumor promotion mechanisms in LoVo cells. We suggest that miR-223 may be a new target for colon cancer early diagnosis and treatment
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