MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2.
This study aimed to understand the exact function and potential mechanism of miR-4500 in colorectal cancer (CRC). In this study, the expression of miR-4500 was decreased in both CRC cells and tissues, and downregulated miR-4500 indicated advanced tumor stage and poor survival. By bisulfite sequencing analysis, we found that the CpG island in the promoter region of miR-4500 was hypermethylated in CRC cells and tissues compared with normal control cells and non-tumor tissues, respectively. Functionally, gain- and loss-of-function analyses indicated the tumor suppressor role of miR-4500: it suppressed cell proliferation, cell cycle progression, migration, and invasion. Predictive algorithms and experimental analyses identified HMGA2 as a direct target of miR-4500. Reintroducing HMGA2 impaired the inhibitory effects of miR-4500 on cell growth and motility. Clinically, higher HMGA2 protein expression in CRC tissues was associated with advanced tumor stage and poor survival. An inverse correlation was found between miR-4500 levels and HMGA2 protein expression. Taken together, this study provides the first evidence that miR-4500 functions as a novel tumor suppressor in the miR-4500/HMGA2 axis in colorectal carcinogenesis, and restoring miR-4500 expression might represent a promising therapeutic strategy for CRC.
a Guangdong Key Laboratory for Research and Development of Natural Drugs , Guangdong Medical University , Zhanjiang, Guangdong Province , China.|b The Second Clinical College of Guangdong Medical University , Zhanjiang, Guangdong Province , China.
Feng Yan
FY
Yu
c Zhanjiang People's Central Hospital , Zhanjiang, Guangdong Province , China.
Yun
Y
Tu
a Guangdong Key Laboratory for Research and Development of Natural Drugs , Guangdong Medical University , Zhanjiang, Guangdong Province , China.
Ying
Y
Deng
a Guangdong Key Laboratory for Research and Development of Natural Drugs , Guangdong Medical University , Zhanjiang, Guangdong Province , China.
Cancan
C
Guo
a Guangdong Key Laboratory for Research and Development of Natural Drugs , Guangdong Medical University , Zhanjiang, Guangdong Province , China.
Jue
J
Ning
a Guangdong Key Laboratory for Research and Development of Natural Drugs , Guangdong Medical University , Zhanjiang, Guangdong Province , China.
Yuzhen
Y
Zhu
d Department of Pharmacology , Guangdong Medical University , Zhanjiang, Guangdong Province , China.
Xiaohua
X
Lv
a Guangdong Key Laboratory for Research and Development of Natural Drugs , Guangdong Medical University , Zhanjiang, Guangdong Province , China.
Hua
H
Ye
D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D025743:HMGA2 Protein / Q000235:genetics* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011379:Prognosis
D025743:HMGA2 Protein; D035683:MicroRNAs
Colorectal cancer; HMGA2; cell proliferation; invasion; methylation; miR-4500; prognosis
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