Six2 is negatively correlated with prognosis and facilitates epithelial-mesenchymal transition via TGF-β/Smad signal pathway in hepatocellular carcinoma

Wan, Zhenghua; Ma, Yunhan; Jiang, Tianyi; Lin, Yun-Kai; Shi, Yuanyuan; Tan, Ye-Xiong; Dong, Lixue; Wang, Hongyang

doi:10.1016/j.hbpd.2019.09.005

Cited by 12 publications

(8 citation statements)

References 33 publications

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“…TGF-β is a multifunctional cytokine that plays a role in various cancers, including hepatic, gastric, and colon cancers [29][30][31]. Furthermore, the TGFβ pathway is associated with poor prognosis in hepatocellular carcinoma, clear cell renal carcinoma, and colorectal cancer [32][33][34]. The serum level of TGF-β is significantly increased in osteosarcoma patients [12], but no study has investigated the role of TGF-β in the pathogenesis of this cancer to date.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: TGF-β is associated with poor prognosis and promotes osteosarcoma progression via PI3K/Akt pathway activation

Zhang

2020

Cell Cycle

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Transforming growth factor beta (TGF-β) is a multifunctional cytokine with important functions in cell proliferation and differentiation. TGF-β is highly expressed in several types of cancers and promotes tumor invasion and metastasis. However, the role of TGF-β in osteosarcoma progression is poorly understood. In the present study, we found that TGF-β is highly expressed in osteosarcoma cells and tissues, and is associated with high Ennecking stage (P = 0.033), metastasis, and recurrence. TGF-β-knockdown osteosarcoma cell lines were established using siRNA (si-TGF-β). Cells transfected with si-TGF-β exhibited significantly reduced proliferation, migration/invasion, and colony formation abilities, and increased levels of cell apoptosis. In addition, si-TGF-β treatment reduced spheroid size, the ratio of CD133-positive cells, and expression of SOX-2, Nanog, and Oct-3/4 in osteosarcoma cells. Mechanistically, PI3K/mTOR phosphorylation is inhibited by TGF-β knockdown. Pretreatment with 25 µM LY294002, a PI3K-specific inhibitor, further enhanced the si-TGF-β-induced suppression of osteosarcoma progression. Taken together, these results reveal a novel role for TGF-β in osteosarcoma progression and modulation of stemness-related traits and indicate that TGF-β may be of value as a therapeutic target for the treatment of osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: TGF-β is associated with poor prognosis and promotes osteosarcoma progression via PI3K/Akt pathway activation

Zhang

2020

Cell Cycle

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“…Intercellular communication is an important characteristic of tumor progression. Mounting evidence has pointed out that cancer exosomes or extracellular vesicles (EVs) participate in the regulation of epithelial to mesenchymal transition (EMT), which is a crucial step for cancer metastasis [ 11 , 12 ]. And miRNAs are the most predominant RNA species in exosomes.…”

Section: Introductionmentioning

confidence: 99%

High-metastatic cancer cells derived exosomal miR92a-3p promotes epithelial-mesenchymal transition and metastasis of low-metastatic cancer cells by regulating PTEN/Akt pathway in hepatocellular carcinoma

et al. 2020

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Exosomes play an important role in intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). However, cellular communication between heterogeneous HCC cells with different metastatic potentials and the resultant cancer progression are not fully understood in HCC. Here, HCC cells with high-metastatic capacity (97hm and Huhm) were constructed by continually exerting selective pressure on primary HCC cells (MHCC-97H and Huh7). Through performing exosomal miRNA sequencing in HCC cells with different metastatic potentials (MHCC-97H and 97hm), many significantly different miRNA candidates were found. Among these miRNAs, miR-92a-3p was the most abundant miRNA in the exosomes of highly metastatic HCC cells. Exosomal miR92a-3p was also found enriched in the plasma of HCC patient-derived xenograft mice (PDX) model with high-metastatic potential. Exosomal miR-92a-3p promotes epithelial-mesenchymal transition (EMT) in recipient cancer cells via targeting PTEN and regulating its downstream Akt/Snail signaling. Furthermore, through mRNA sequencing in HCC cells with different metastatic potentials and predicting potential transcription factors of miR92a-3p, upregulated transcript factors E2F1 and c-Myc were found in high-metastatic HCC cells promote the expression of cellular and exosomal miR-92a-3p in HCC by directly binding the promoter of its host gene, miR17HG. Clinical data showed that a high plasma exosomal miR92a-3p level was correlated with shortened overall survival and disease-free survival, indicating poor prognosis in HCC patients. In conclusion, hepatoma-derived exosomal miR92a-3p plays a critical role in the EMT progression and promoting metastasis by inhibiting PTEN and activating Akt/Snail signaling. Exosomal miR92a-3p is a potential predictive biomarker for HCC metastasis, and this may provoke the development of novel therapeutic and preventing strategies against metastasis of HCC.

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“…Wang et.al found that Six2 promotes metastasis by decreasing E-cadherin and regulating epithelial-mesenchymal transition in breast cancer [13]. Similar results were also found in lung cancer, hepatocellular cancer, and renal cell carcinoma [14][15][16]. Another research focusing on Six2 downstream effectors found out that Six2 directly bound with SOX2 enhancer, thus upregulating SOX2 and NANOG expression and enabling tumor metastatic colonization [17].…”

Section: Introductionmentioning

confidence: 59%

Comprehensive analysis of Six2-mediated transcriptional regulatory network in ccRCC

Tian

Yang

et al. 2022

Preprint

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BackgroundSix2, a transcription factor, exerts an oncogenic role in clear cell renal cell carcinoma (ccRCC). Increased Six2 expression could enhance cancer metastasis. However, the regulatory action of Six2 remains unclear in cancer. The purpose of this study is to analyze the regulatory pattern and potential downstream effectors of Six2.MethodsFirstly, transcriptional data in TCGA-KIRC cohorts was used to analyze the relationship between Six2 expression and clinical information. Then, we analyzed Six2-related differentially expressed genes (DEGs) and constructed a prognostic model using the Lasso-Cox algorithm by integrating Six2 ChIP data and co-expressed genes. Next, we analyzed the clinical significance of this model and examined the DEGs between the high-and low-risk group. Finally, we intersected the GO and KEGG pathway results between Six2-related DEGs and risk-related DEGs to reveal biological functions in which Six2 is involved.ResultsSix2 was increased in RCC cells compared with normal kidney cells and upregulated Six2 was positively linked with clinical stage, M stage, and worse survival. Potential downstream effectors and biological functions regulated by Six2 were identified using in silico analysis. Meanwhile, a risk model based on 8 Six2 target genes was established to classify ccRCC patients into high-and-low groups. This risk model showed a reliable ability to forecast the overall survival of ccRCC patients. Shared enriched pathways were found between the Six2 high-and low-expression and risk groups, such as epithelial-to-mesenchymal transition, PI3K-Akt pathway, etc.ConclusionOur findings provide a promising prognostic indicator for ccRCC patients and help better understand the transcriptional role of Six2 in ccRCC.

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Six2 is negatively correlated with prognosis and facilitates epithelial-mesenchymal transition via TGF-β/Smad signal pathway in hepatocellular carcinoma

Cited by 12 publications

References 33 publications

RETRACTED ARTICLE: TGF-β is associated with poor prognosis and promotes osteosarcoma progression via PI3K/Akt pathway activation

RETRACTED ARTICLE: TGF-β is associated with poor prognosis and promotes osteosarcoma progression via PI3K/Akt pathway activation

High-metastatic cancer cells derived exosomal miR92a-3p promotes epithelial-mesenchymal transition and metastasis of low-metastatic cancer cells by regulating PTEN/Akt pathway in hepatocellular carcinoma

Comprehensive analysis of Six2-mediated transcriptional regulatory network in ccRCC

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