December 20, 2024Cell Biology and Toxicology9 citationsOpen Access

M6A modification-mediated LIMA1 promotes the progression of hepatocellular carcinoma through the wnt-βcatenin/Hippo pathway

CZChao ZhangMinistry of Ecology and Environment XWXiaoxiao WangZhejiang Center for Disease Control and Prevention HSHuangqin SongShanxi Medical University

Structured PICO

Population

Human hepatocellular carcinoma (HCC) tissue samples (48 pairs for IHC, 17 pairs for Western blot), TCGA dataset (371 HCC samples, 160 normal hepatic tissue samples), multiple HCC cell lines (HepG2, HepG2 2.15, Hep3B2.1-7, SUN-387, THLE-3, MHCC-97L, MHCC-97H, Huh 7), and 4-6 week old male nude mice xenograft models.

Intervention

LIMA1 silencing (siRNA/shRNA) or overexpression, METTL3 silencing/overexpression, and beta-catenin silencing.

Comparator

Negative controls (si-NC, sh-NC, and empty vector).

Outcome

HCC cell proliferation, migration, invasion, stemness, and tumor growth in nude mice.surrogate

LIMA1 promotes hepatocellular carcinoma progression via the Wnt-β-catenin and Hippo pathways and is regulated by METTL3-mediated m6A modification, highlighting a potential therapeutic target.

Abstract

Hepatocellular carcinoma (HCC), considered as one of the most common and lethal cancers worldwide, has drawn significant attention from researchers.Extensively studied diverse cancers, the function of LIMA1 in tumorigenesis and cancer progression remains ambiguous.. Moreover, the role of LIMA1 in HCC remains controversial. The expression difference of LIMA1 in hepatocellular carcinoma, which was verified by TMT quantitative proteomics, immunohistochemistry, western blot, and the TCGA database, has been investigated in this study. Demonstrated by using transwell, cck8, sphere formation, and other experiments, the effects of LIMA1 on the migration, proliferation, stemness, and other aspects of hepatocellular carcinoma were significant. Moreover, the effect of LIMA1 on the wnt-βcatenin/Hippo pathway was revealed by using RNA sequencing and western blot, and the relationship between LIMA1 and βcatenin was verified by using COIP. Finally, the effect of m6a modification on LIMA1 was further verified using Western blotting, actinomycin D and MeRip experiments. In HCC tissues and several HCC cell lines, LIMA1 was expressed at a relatively high level.LIMA1 positively regulated the invasion, migration, proliferation and stemness of hepatocellular carcinoma, and silencing of LIMA1 inhibited the tumorigenic ability of HCC cells in nude mice. Moreover, it was shown that LIMA1 can have an impact on the wnt-β-catenin/Hippo pathway. And silencing β-catenin suppressed the invasion, migration, proliferation and stemness of hepatocellular carcinoma cells mediated by LIMA1. Finally, it was further verified that the activation of LIMA1 in hepatocellular carcinoma cells is due to m6-methyladenosine methylation that is dependent on METTL3. In HCC, LIMA1 functions as a tumor promoter and engages with the WNT-β-catenin and Hippo signaling pathways,, affecting the characteristics of tumor cells. LIMA1 expression is regulated by METTL3-mediated m6A modification, leading to its high expression in HCC. Our research presents a hopeful objective for the detection and therapy of HCC. 1.The m6A modification mediated by METTL3 can promote the high expression of LIMA1 in hepatocellular carcinoma. 2.LIMA1 can bind to β-catenin, promoting its nuclear translocation and activating downstream signaling pathways. Additionally, LIMA1 can enhance the expression of key proteins YAP/TAZ in the Hippo pathway. 3.LIMA1 plays a crucial role in EMT, proliferation, invasion, and stemness in hepatocellular carcinoma, thereby promoting the progression of the disease.

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