An integrin beta4-EGFR unit promotes hepatocellular carcinoma lung metastases by enhancing anchorage independence through activation of FAK–AKT pathway

Leng, Chao; Zhang, Zhanguo; Chen, Weixun; Luo, Hongping; Song, Jia; Wang, Dong; Zhu, X.H; Chen, Xiaoping; Liang, Huifang; Zhang, Bixiang

doi:10.1016/j.canlet.2016.03.023

Cited by 74 publications

(61 citation statements)

References 38 publications

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“…This result was consistent with previous mechanistic work, which demonstrated that ITGB4 can promote activation of the MET protooncogene receptor tyrosine kinase, epidermal growth factor receptor, focal adhesion kinase, SRC protooncogene nonreceptor tyrosine kinase, phosphoinositide 3-kinase, AKT serine/threonine kinase (AKT), mitogen-activated protein kinase kinase 1/2, mitogen-activated protein kinase (ERK) 1/2, and ras homolog family member A signaling pathways that are known to enhance tumor progression (13)(14)(15). Importantly, ITGB4 has been previously shown to be enriched in TNBC breast cancer patient tissues (16).…”

supporting

confidence: 91%

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

Bierie

Pierce

Kroeger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

281

213

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Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin-β4 (ITGB4), can be used to enable stratification of mesenchymallike triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4+ cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival. Mechanistically, we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC.cancer | heterogeneity | EMT | mesenchymal | ITGB4

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supporting

confidence: 91%

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

Bierie

Pierce

Kroeger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

281

213

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“…Pluripotency is the ability of a cell to differentiate into any cell type and is a unique characteristic of embryonic stem cells (ESCs)19. Pluripotency transcription factors such as Sox2, Nanog, KLF4 and c-MYC, etc have been also suggested to be oncogenes and may be implicated in the development of several cancers involving multiple signaling pathways including PI3K, AKT, etc2021222324. Previous reports have shown that the aforementioned transcription factors are regulated, at least in part, by pluripotency factors1925.…”

mentioning

confidence: 99%

Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma

Liu

et al. 2017

Sci Rep

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Integrin β4 (ITGB4) is a transmembrane receptor involved in tumorigenesis and the invasiveness of many cancers. However, its role in hepatocellular carcinoma (HCC), one of the most prevalent human cancers worldwide, remains unclear. Here, we examined the involvement of ITGB4 in HCC and explored the underlying mechanisms. Real-time PCR and immunohistochemical analyses of tissues from 82 patients with HCC and four HCC cell lines showed higher ITGB4 levels in tumor than in adjacent non-tumor tissues and in HCC than in normal hepatic cells. Silencing of ITGB4 repressed cell proliferation, colony forming ability and cell invasiveness, whereas ectopic expression of ITGB4 promoted the proliferation and invasion of HCC cells and induced epithelial to mesenchymal transition (EMT) in parallel with the upregulation of Slug, as shown by transwell assays, WB and immunocytochemistry. Knockdown of Slug reduced cell viability inhibited invasion and reversed the effects of ITBG4 overexpression on promoting EMT, and AKT/Sox2-Nanog may also be involved. In a xenograft tumor model induced by injection of ITGB4-overexpressing cells into nude mice, ITGB4 promoted tumor growth and metastasis to the lungs. Taken together, our results indicate that ITGB4 plays a tumorigenic and pro-metastatic role mediated by Slug and suggest IGTB4 could be a prognostic indicator or a therapeutic target in patients with HCC.

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“…Integrin β4 has shown to interact with EGFR in a ligand‐independent manner and mediate the activation of EGFR pathway . The expression of TSLP was regulated through EGFR transactivation in human and mouse keratinocytes .…”

Section: Resultsmentioning

confidence: 99%

“…Since the fundamental findings of Moro et al who first showed transactivation of EGFR by integrins, a huge body number of researches work has have confirmed this pathway . ITGB4 is also observed to interact with EGFR in a ligand manner in hepatocellular carcinoma cell line . ITGB4 and EGFR have previously been demonstrated to colocalize, which impairs the mobility of EGFR in the plasma membrane and reduces the binding efficiency of the ligand to EGFR .…”

Section: Discussionmentioning

confidence: 97%

Airway epithelial ITGB4 deficiency in early life mediates pulmonary spontaneous inflammation and enhanced allergic immune response

Tang

Lin

et al. 2020

J Cellular Molecular Medi

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Lung immune responses to respiratory pathogens and allergens are initiated in early life which will further influence the later onset of asthma. The airway epithelia form the first mechanical physical barrier to allergic stimuli and environmental pollutants, which is also the key regulator in the initiation and development of lung immune response. However, the epithelial regulation mechanisms of early‐life lung immune responses are far from clear. Our previous study found that integrin β4 (ITGB4) is decreased in the airway epithelium of asthma patients with specific variant site. ITGB4 deficiency in adult mice aggravated the lung Th2 immune responses and enhanced airway hyper‐responsiveness (AHR) with a house dust mite (HDM)‐induced asthma model. However, the contribution of ITGB4 to the postnatal lung immune response is still obscure. Here, we further demonstrated that ITGB4 deficiency following birth mediates spontaneous lung inflammation with ILC2 activation and increased infiltration of eosinophils and lymphocytes. Moreover, ITGB4 deficiency regulated thymic stromal lymphopoietin (TSLP) production in airway epithelial cells through EGFR pathways. Neutralization of TSLP inhibited the spontaneous inflammation significantly in ITGB4‐deficient mice. Furthermore, we also found that ITGB4 deficiency led to exaggerated lung allergic inflammation response to HDM stress. In all, these findings indicate that ITGB4 deficiency in early life causes spontaneous lung inflammation and induces exaggerated lung inflammation response to HDM aeroallergen.

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An integrin beta4-EGFR unit promotes hepatocellular carcinoma lung metastases by enhancing anchorage independence through activation of FAK–AKT pathway

Cited by 74 publications

References 38 publications

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma

Airway epithelial ITGB4 deficiency in early life mediates pulmonary spontaneous inflammation and enhanced allergic immune response

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