MEIS2C and MEIS2D promote tumor progression via Wnt/β-catenin and hippo/YAP signaling in hepatocellular carcinoma

Abstract

Background MEIS2 has been identified as one of the key transcription factors in the gene regulatory network in the development and pathogenesis of human cancers. Our study aims to identify the regulatory mechanisms of MEIS2 in hepatocellular carcinoma (HCC), which could be targeted to develop new therapeutic strategies. Methods The variation of MEIS2 levels were assayed in a cohort of HCC patients. The proliferation, clone-formation, migration, and invasion abilities of HCC cells were measured to analyze the effects of MEIS2C and MEIS2D (MEIS2C/D) knockdown with small hairpin RNAs in vitro and in vivo. Chromatin immunoprecipitation (ChIP) was performed to identify MEIS2 binding site. Immunoprecipitation and immunofluorescence assays were employed to detect proteins regulated by MEIS2. Results The expression of MEIS2C/D was increased in the HCC specimens when compared with the adjacent noncancerous liver (ANL) tissues. Moreover, MEIS2C/D expression negatively correlated with the prognosis of HCC patients. On the other hand, knockdown of MEIS2C/D could inhibit proliferation and diminish migration and invasion of hepatoma cells in vitro and in vivo. Mechanistically, MESI2C activated Wnt/β-catenin pathway in cooperation with Parafibromin (CDC73), while MEIS2D suppressed Hippo pathway by promoting YAP nuclear translocation via miR-1307-3p/LATS1 axis. Notably, CDC73 could directly either interact with MEIS2C/β-catenin or MEIS2D/YAP complex, depending on its tyrosine-phosphorylation status. Conclusions Our studies indicate that MEISC/D promote HCC development via Wnt/β-catenin and Hippo/YAP signaling pathways, highlighting the complex molecular network of MEIS2C/D in HCC pathogenesis. These results suggest that MEISC/D may serve as a potential novel therapeutic target for HCC.

Sonic Hedgehog signaling pathway in gynecological and genitourinary cancer (Review)

“…A myeloid ecotropic insertion site 2 (MEIS2) transcription factor is another molecule that activates the expression of the SHH gene for patterning the mandibular arch during fetal development, as observed by Fabik et al ( 35 ) in a mouse model. The upregulation of MEIS2 was observed in castration-resistant prostate cancer (PC) ( 94 ) and hepatocellular carcinoma, where its isoform MEIS2C activates the Wnt/β-catenin pathway by interacting with the CDC73 molecule ( 95 ). The hypoxia-inducible factor 1-α (HIF1A) transcription factor is an important molecule triggered by hypoxia in the cells and tissues of fetal and mature organisms.…”

Downregulation of miR-193a-3p is involved in the pathogenesis of hepatocellular carcinoma by targeting CCND1

“…In 2019, Liu et al (2019) found that a low level of miR-193a-3p expression was related to the increased expression of p21-activated kinase 4 (PAK4), p-Slug, and L1 cell adhesion molecule (L1CAM) in non-small cell lung cancer (NSCLC) and that miR-193a-3p inhibited the metastasis of NSCLC by repressing PAK4, p-Slug, and L1CAM. Through MTT assay and cell colony formation experiments, Yu et al (2019) showed that miR-193a-3p was downregulated in colorectal cancer cells, while miR-193a-3p's inhibitors promoted the proliferation and invasion of rectal cells. Recently, many researchers have verified that miR-193a-3p acts as an inhibitor in colon, gastric, and breast cancer because it suppressed the proliferation, migration, and invasion of these cancer cells (Chou et al, 2018;Pekow et al, 2017;Tsai et al, 2016).…”

“…Actually, the ErbB pathway has been shown to participate in the epithelial-mesenchymal transition (EMT) of HCC, and miR-296-5p is able to inhibit EMT in HCC by attenuating ErbB signaling (Shi et al, 2018). In contrast, as a likely target of CCND1 (Karimkhanloo et al, 2017), the Wnt pathway is well-known to be involved in the progression of HCC (Zhu et al, 2019b;Hu et al, 2019;Guan et al, 2019;Zhu et al, 2019a.). However, it was not among the most enriched pathways according to the findings of the KEGG pathway analysis.…”

Upregulation of miR-1254 promotes Hepatocellular Carcinoma Cell Proliferation, Migration, and Invasion via Inactivation of the Hippo-YAP signaling pathway by decreasing PAX5

“…Research supports that the Hippo signaling pathway is important in inhibition of tissue overgrowth and tumorigenesis [23]. The dysregulation of the Hippo pathway affects human cancers such as prostate, liver, colorectal, and gastric cancer [24][25][26][27]. The Hippo pathway includes a large tumor suppressor (LATS) kinase that causes the phosphorylation of yes-associated protein (YAP).…”