SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET

He, Qiaojun; Lin, Zhuoying; Wang, Zhihui; Huang, Wenjie; Tian, Dean; Liu, Mei; Xia, Limin

doi:10.1038/s41388-020-01500-y

Cited by 37 publications

(27 citation statements)

References 53 publications

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“…YAP1 is in hyperactive status and considered to be an oncogene in several types of solid tumors, including HCC ( 19 ). SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 ( 20 ). LncRNA B4GALT1-AS1 facilitates colon cancer cell stemness via recruiting YAP1 to the nucleus and enhancing YAP1 transcriptional activity ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation

Hong

Wang

et al. 2021

Front. Oncol.

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BackgroundHepatocellular carcinoma (HCC) remains a major global health burden due to its high prevalence and mortality. Emerging evidence reveals that microRNA (miRNA) plays a vital role in cancer pathogenesis and is widely involved in the regulation of signaling pathways via their targeting of downstream genes. MiR-21-3p, a liver-enriched miRNA, and SMAD7, the negative regulator of the TGF-β signaling pathway, likely exert a vital influence on HCC progression.AimsHere, we explore the role of the miR-21-3p-SMAD7/YAP1 axis on HCC pathogenesis.MethodsMiRNA microarray analysis was performed for miRNA screening. The dual-luciferase assay was adopted for target verification. Expression of miRNA and related genes were quantified via qRT-PCR, western blotting, and immunohistochemical staining. Flow cytometry and the transwell migration assay were used to detail cell apoptosis, invasion and metastases. Rat models were established to explore the role of the miR-21-3p-SMAD7/YAP1 axis in hepatocarcinogenesis. Bioinformatics analysis was conducted for exploring genes of clinical significance.ResultsMiR-21-3p levels were found to be significantly elevated in hepatocellular carcinoma and indicate poor overall survival. High miR-21-3p levels were associated with advanced tumor stages (P = 0.029), in particular T staging (P = 0.026). Low SMAD7/high YAP1 levels were confirmed in both HCC and rat models with advanced liver fibrosis and cirrhosis. Besides, SMAD7 was demonstrated to be the direct target of miR-21-3p. The effect of MiR-21-3p on tumor phenotypes and YAP1 upregulation could be partly reversed via the restoration of SMAD7 expression in HCC cell lines. Overexpression of YAP1 after miR-21-3p upregulation promoted expression of nuclear transcription effector connective tissue growth factor. Co-survival analysis indicated that lower miR-21-3p/higher SMAD7 (P = 0.0494) and lower miR-21-3p/lower YAP1 (P = 0.0379) group patients had better overall survival rates. Gene Set Variation Analysis revealed that gene sets related to miR-21-3p and SMAD7 were significantly associated with the TGF-β signaling pathway in HCC.ConclusionMiR-21-3p promotes migration and invasion of HCC cells and upregulation of YAP1 expression via direct inhibition of SMAD7, underscoring a major epigenetic mechanism in the pathogenesis of HCC.

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Section: Introductionmentioning

confidence: 99%

MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation

Hong

Wang

et al. 2021

Front. Oncol.

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“…SIX4 expression has been detected in non-small cell lung ( Tang et al, 2019 ), breast ( Sun et al, 2020 ), colorectal ( Li et al, 2017 ; Sun et al, 2019 ), and hepatocellular cancers ( He et al, 2020 ). Over- or ectopic expression of SIX4 promoted metastasis by inducing epithelial-to-mesenchymal transition and angiogenesis ( Sun et al, 2019 ).…”

Section: Biomarkers and Prognostic Indicators In Cancermentioning

confidence: 99%

“…Over- or ectopic expression of SIX4 promoted metastasis by inducing epithelial-to-mesenchymal transition and angiogenesis ( Sun et al, 2019 ). Furthermore, significant correlations have been identified between expression levels of SIX4 , tumor cell metastasis, and poor patient prognosis ( Li et al, 2017 ; Tang et al, 2019 ; Sun et al, 2019 , 2020 ; He et al, 2020 ). To date, few studies have analyzed SIX5 function in cancer ( Table 2 ).…”

Section: Biomarkers and Prognostic Indicators In Cancermentioning

confidence: 99%

“…However, cyclin D1 expression has been shown to be dependent upon Six2 in the developing palate ( Okello et al, 2017 ) while studies in kidney progenitor cells have detected Six2 binding sites in the ccnd1 (cyclin D1) promoter region ( O’Brien et al, 2018 ). Six6, along with Dachous (Dach) proteins, promoted cell proliferation by directly repressing the expression of cyclin-dependent kinase inhibitors ( Li et al, 2002 ; Iglesias et al, 2014 ) while Six4 regulated the expression of Yap1 and c-Met to promote cell proliferation in HCC ( He et al, 2020 ). Cell cycle control by SIX proteins is also accomplished via protein interactions.…”

Section: Common Themesmentioning

confidence: 99%

“…One of the downstream targets of c-Met/HGF is Snail, a known repressor of E -cadherin ( Wang et al, 2020 ). It has been demonstrated that SIX4 could directly activate c-Met expression in HCC providing a mechanism for promoting EMT, cell migration, and metastasis ( He et al, 2020 ). In support of the finding in HCC, both Six1 and Six4 have been shown to activate met expression in both embryonic mouse and zebrafish and this activation was required for skeletal muscle precursor cell migration ( Grifone et al, 2005 ; Talbot et al, 2019 ).…”

Section: Common Themesmentioning

confidence: 99%

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The SIX Family of Transcription Factors: Common Themes Integrating Developmental and Cancer Biology

Meurer

Ferdman

Belcher

et al. 2021

Front. Cell Dev. Biol.

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The sine oculis (SIX) family of transcription factors are key regulators of developmental processes during embryogenesis. Members of this family control gene expression to promote self-renewal of progenitor cell populations and govern mechanisms of cell differentiation. When the function of SIX genes becomes disrupted, distinct congenital defects develops both in animal models and humans. In addition to the embryonic setting, members of the SIX family have been found to be critical regulators of tumorigenesis, promoting cell proliferation, epithelial-to-mesenchymal transition, and metastasis. Research in both the fields of developmental biology and cancer research have provided an extensive understanding of SIX family transcription factor functions. Here we review recent progress in elucidating the role of SIX family genes in congenital disease as well as in the promotion of cancer. Common themes arise when comparing SIX transcription factor function during embryonic and cancer development. We highlight the complementary nature of these two fields and how knowledge in one area can open new aspects of experimentation in the other.

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Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

Yang

Huo

et al. 2021

Clinical & Translational Med

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Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates. Methods The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS 2 ), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor. Results PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS 2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS 2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo. Conclusions Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS 2 as a PLAGL2 inhibitor in patients with HCC.

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SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET

Cited by 37 publications

References 53 publications

MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation

MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation

The SIX Family of Transcription Factors: Common Themes Integrating Developmental and Cancer Biology

Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

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