MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Abstract

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.Abbreviations: CRC, Colorectal cancer; HMGA2, high mobility group AT-hook 2; 5-aza, 5-aza-2 0 -deoxycytidine

High mobility group protein A2 overexpression indicates poor prognosis for cancer patients: a meta-analysis

“…These studies were mainly conducted in East Asia, Europe, and the United States of America. The cancer types studied were: gastric cancer (GC) [ 16 – 18 ], breast cancer (BC) [ 10 , 19 ], hepatocellular carcinoma (HCC) [ 11 , 13 ], colorectal cancer (CRC) [ 14 , 20 , 21 ], ovarian cancer (OC) [ 22 , 23 ], nasopharyngeal carcinoma (NPC) [ 24 , 25 ], esophageal carcinoma (EC) [ 26 , 27 ], head and neck squamous cell carcinoma (HNSCC) [ 28 – 30 ], clear cell renal cell carcinoma [ 12 ], intrahepatic cholangiocarcinoma [ 31 ], glioblastoma [ 32 ], gallbladder adenocarcinoma [ 33 ], melanoma [ 34 ], non-small-cell lung cancer [ 35 ], and bladder cancer [ 36 ]. HMGA2 was detected using immunohistochemistry (IHC) (24 studies), reverse transcription-polymerase chain reaction (RT-PCR) (2 studies), or quantitative real-time polymerase chain reaction (qRT-PCR) (3 studies).…”

Screening and functional prediction of differentially expressed circRNAs in proliferative human aortic smooth muscle cells

“…Studies have shown that HMGA2 is overexpressed in cancer cells and promotes angiogenesis . And miR‐4500, miR‐98‐5p and miR‐485‐5p have been reported to directly target the 3′‐UTR of HMGA2 in other cell‐type studies. These cases profile the bright prospects of hsa_circ_0002579, which acts as a ceRNA molecule interacting with miRNAs to regulate the proliferation of HASMCs by targeting HMGA2.…”

Promotion of BZW2 by LINC00174 through miR-4500 inhibition enhances proliferation and apoptosis evasion in laryngeal papilloma

“…In this study, miR-4500 was identified as a target of BZW2. Previous studies have demonstrated the roles of miR-4500 in the occurrence and development of various cancers including hepatoma, non-small cell lung cancer (NSCLC) and colorectal cancer [22][23][24][25]. For instance, Zhang and colleagues have demonstrated the low expressions of miR-4500 associated with cancer cell proliferation in NSCLC [22].…”