Abstract
Hepatocellular carcinoma (HCC) represents a malignant tumor predominantly arising in the setting of cirrhosis and is the third most common cause of cancer-associated death on a global scale. The heterogeneous nature of HCC and limited well-recognized biomarkers may contribute to poor patient prognosis and treatment failure. In this study, we identified expression pattern of microRNA-202-3p (miR-202-3p) in HCC and characterized its functional role as well as related mechanisms. First, we collected 50 HCC tissues and 38 normal liver tissues, and after bioinformatics prediction, the expression of miR-202-3p and KDM3A was determined in the tissues. We found lowly expressed miR-202-3p and overexpressed KDM3A in HCC tissues. Then, dual-luciferase reporter gene assay was employed to test the presence of miR-202-3p binding sites in the 3’UTR of KDM3A and chromatin immunoprecipitation (ChIP) assay to homeobox A1 (HOXA1) interaction with KDM3A and MEIS3. It has been confirmed that miR-202-3p negatively regulated KDM3A responsible for increasing the expression of HOXA1 by eliminating the histone H3 lysine 9 (H3K9)me2 in HCC cells. HOXA1 could evidently increase H3K4me1 and H3K27ac enrichment in the MEIS3 enhancer region and enhance the expression of MEIS3. Functional assays were also performed with the results showing that upregulated miR-202-3p or downregulated KDM3A retarded HCC cell viability, migration, and invasion. In addition, HepG2 cells were xenografted into nude mice, and we demonstrated that upregulated miR-202-3p reduced the growth of human HCC cells in vivo. Taken together, the present study elicits a novel miR-202-3p/KDM3A/HOXA1/MEIS3 pathway in HCC, potentiating an exquisite therapeutic target for HCC.
Highlights
Hepatocellular carcinoma is the sixth most prevalent malignancy and ranks third in overall global cancer-associated mortality worldwide, accounting for an estimated one million causalities across the globe in 2030 (Villanueva, 2019)
The findings revealed that the elevated expression of miR202-3p by miR-202-3p mimic diminished the expression of KDM3A at the mRNA level and protein level (Western blot analysis) in HepG2 cells (Figures 1I,J), and retarded HepG2 cell viability, migration, and invasion, demonstrated by MTT assay and transwell chamber systems (Figures 1K,L)
Statistics show that liver cancer ranks the seventh prevalently occurring malignancy and is considered as a leading cause of death related to cancers, accounting for 4.7 and 8.2%, respectively, in both sexes on a global scale as reported in 2018 (Bray et al, 2018)
Summary
Hepatocellular carcinoma is the sixth most prevalent malignancy and ranks third in overall global cancer-associated mortality worldwide, accounting for an estimated one million causalities across the globe in 2030 (Villanueva, 2019). KDM3A has exhibited ability to transcriptionally increase the expression of HOXA1 by erasing the H3K9me, promoting the cell cycle progression in cancer cells (Cho et al, 2012). MEIS3 directly targets 3-phosphoinositide-dependent PDK1, a recognized kinase involved in the PI3K/Akt signaling pathway, and regulates cell survival (Liu et al, 2010). In light of these findings, we aimed to elucidate the functional roles of miR-202, KDM3A, HOXA1, and MEIS3 in HCC and their interactions. Our results provided new mechanistic insights for a better understanding of hepatotumorigenesis and revealed the functionality of the miR-202-3p/KDM3A/HOXA1/MEIS3 pathway as a potential therapeutic target for HCC
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