Genes Regulating Epithelial Polarity Are Critical Suppressors of Esophageal Oncogenesis

Li, Xiu Min; Wang, Hui; Zhu, Lingling; Zhao, Runzhen; Ji, Hong

doi:10.7150/jca.11709

Cited by 8 publications

(6 citation statements)

References 61 publications

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“…ESCC is the most prevalent histopathologic subtype of EC in central regions of China, especially in Henan province [ 14 ]. Despite of the recent rapid advances in the diagnosis and treatment, survival of ESCC patients with recurrence or metastasis remains unfavorable [ 15 , 16 ]. The improvement of ESCC survival rate requires a clear understanding of pivotal molecular mechanisms from the initiation and progression of ESCC.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA MALAT1 promotes malignant development of esophageal squamous cell carcinoma by targeting β-cateninviaEzh2

Wang

Zhu

et al. 2016

Oncotarget

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Evidences have shown that lncRNAs involve in the initiation and progression of various cancers including esophageal squamous cell carcinoma (ESCC). The aberrant expression of lncRNA MALAT1 was investigated in 106 paired ESCC tissues and adjacent non-cancerous tissues by qRT-PCR. Down-regulated MALAT1 and Ezh2 over-expression plasmid were constructed respectively to analyze the expression of β-catenin, Lin28 and Ezh2 genes. We found that the MALAT1 expression level was higher in human ESCC tissues (P=0.0011), which was closely correlated with WHO grade (P=0.0395, P=0.0331), lymph node metastasis (P=0.0213) and prognosis (P=0.0294). Silencing of MALAT1 expression inhibited cell proliferation, migration and tumor sphere formation, while increasing cell apoptosis of esophageal cancer in vitro. Down-regulation of MALAT1 decreased the expression of β-catenin, Lin28 and Ezh2 genes, while over-expressed Ezh2 combined with MALAT1 down-regulation completely reversed the si-MALAT1-mediated repression of β-catenin and Lin28 in esophageal cancer cells. Animal experiments showed that knockdown of MALAT1 decreased tumor formation and improved survival. MALAT1 promotes the initiation and progression of ESCC, suggesting that inhibition of MALAT1 might be a potential target for treatment of ESCC.

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Section: Discussionmentioning

confidence: 99%

Long noncoding RNA MALAT1 promotes malignant development of esophageal squamous cell carcinoma by targeting β-cateninviaEzh2

Wang

Zhu

et al. 2016

Oncotarget

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“…PAR complex, an evolutionarily conserved protein complex among multicellular organisms from worms to humans, is important for maintenance of epithelial polarity and its dislocation or dissociation is involved in epithelial tumorigenesis and metastasis [11, 12]. As reported, loss of Par3, a key component of the PAR complex, is found to be tightly correlated with lymph node metastasis in esophageal squamous cell carcinoma [13]. Our previous work also demonstrated that dissociation of PAR complex by Shp2 contributes to metastasis in prostate cancers via induction of epithelial-to-mesenchymal transition (EMT) [14].…”

Section: Introductionmentioning

confidence: 99%

Elevated expression of Gab1 promotes breast cancer metastasis by dissociating the PAR complex

Xiao

Peng

Yang

et al. 2019

J Exp Clin Cancer Res

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BackgroundBreast cancer (BCa) remains as the second leading cause of cancer-related death in women worldwide. The majority of the deaths are due to its progression to metastatic BCa. Although Grb2-associated binding protein 1 (Gab1) has been implicated in tumor proliferation and metastasis in multiple tumors including colorectal cancer, hepatocellular carcinoma and ovarian cancer, whether and how it regulates BCa metastasis are still poorly understood.MethodsWestern blot assay and immunohistochemical (IHC) staining were performed to assess expression of Gab1 in primary and metastatic BCa clinical samples. Biological function assay studies in vitro and in vivo were employed to investigate the functions of Gab1 during BCa metastasis. Co-immunoprecipitation (co-IP) assessment, western blot assay and immunofluorescence (IF) staining were carried out to investigate the underlying mechanism for the function of Gab1 on BCa metastasis.ResultsIn this study, we found that expression level of Gab1 was increased significantly in BCa tissue samples compared to that in benign mammary hyperplastic tissues. Furthermore, elevated expression of Gab1 was positively associated with metastasis in HER2 and TNBC subtypes of BCa. In BCa cell line MDA-MB-231 and SK-BR3 cells, stable overexpression of Gab1 promoted, while knockdown of Gab1 inhibited cell migration in vitro and metastasis in vivo. Mechanistically, overexpression of Gab1 enhanced its interaction with Par3, a key component of the polarity-associated partitioning defective (PAR) complex, leading to a dissociation of the PAR complex. Consequently, dissociated PAR complex induced epithelial-to-mesenchymal transition (EMT) for breast tumor metastasis. By restoration assessment, we found that only re-expression of a fully functional Gab1, but not a mutant Gab1 that harbors either Par3 binding-deficiency or Par1b binding-deficiency, could reverse the repressive phenotype of cell migration in vitro and metastasis in vivo due to Gab1 knockdown.ConclusionsOur findings indicate that elevated expression of Gab1 promotes BCa metastasis by dissociating the PAR complex that leads to EMT, implicating a role of Gab1 as a potential biomarker of metastatic BCa. Moreover, inhibition of Gab1 expression might be a promising therapeutic strategy for BCa metastasis.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1025-2) contains supplementary material, which is available to authorized users.

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“…The abnormal localization of claudin-7 promotes cell transformation and regulates E-cadherin expression during tumor progression. 48 , 49 Loss of claudin-7 expression in oral squamous cell carcinoma was associated with high pathological grade, TNM staging, vascular invasion, and regional lymph node involvement. 50 Claudin-7 expression was also significantly associated with histological grade and distant metastasis in breast cancer 51 , 52 and endometrial cancer, 53 and it had prognostic significance.…”

Section: Claudin-7 and Cancer: Causal Correlationmentioning

confidence: 99%

Emerging clinical significance of claudin-7 in colorectal cancer: a review

Wang¹,

Xu²,

Li³

et al. 2018

CMAR

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Tight junctions (TJs) play an important role in maintaining cell polarity and regulating cell permeability. In recent years, many studies have shown that TJ proteins, especially claudin-7, are closely related to inflammation and the development of various malignant tumors. Claudin-7 plays a significant role in maintaining the physiological functions and pathological conditions of the TJ barrier. The dysregulation of claudin-7 plays a tumor suppressor role or conversely has carcinogenic effects in different target tissues or cells, but the exact underlying mechanism is still unclear. In this review, we will summarize the expression pattern of claudin-7 in tumors, focusing on the expression and regulation of claudin-7 in colorectal cancer and discussing the correlation between claudin-7 and invasion, metastasis and epithelial–mesenchymal transition (EMT) in colorectal cancer. The construction of Cldn7−/− mice and conventional claudin-7 knockout mouse models has helped determine the mechanisms by which claudin-7 promotes tumorigenesis. Elucidation of the expression and subcellular localization of claudin-7 under pathological conditions will help develop claudin-7 as a useful biomarker for detecting and diagnosing cancer, and thus may help combat the occurrence, development, and invasion of cancers.

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Genes Regulating Epithelial Polarity Are Critical Suppressors of Esophageal Oncogenesis

Cited by 8 publications

References 61 publications

Long noncoding RNA MALAT1 promotes malignant development of esophageal squamous cell carcinoma by targeting β-cateninviaEzh2

Long noncoding RNA MALAT1 promotes malignant development of esophageal squamous cell carcinoma by targeting β-cateninviaEzh2

Elevated expression of Gab1 promotes breast cancer metastasis by dissociating the PAR complex

Emerging clinical significance of claudin-7 in colorectal cancer: a review

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