Integrin β1 is required for the invasive behaviour but not proliferation of squamous cell carcinoma cells in vivo

Brockbank, E.; Bridges, Jackie; Marshall, Chris; Sahai, Erik

doi:10.1038/sj.bjc.6602255

Cited by 63 publications

(66 citation statements)

References 38 publications

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“…In particular, silenced cells embedded into the 3D matrigel/collagen I matrix organize in spheroids smaller than control ones (data not shown), that do not extend protrusions, whereas control cells give rise to sprouted structures. Consistently, also in the squamous carcinoma A431 cells, b1 integrin silencing gave rise to less invasive tumors (Brockbank et al, 2005). Although we were unable to perform lung colonization assays with the A549 cells, these in vitro data already clearly support the primary role of b1 integrin in regulating lung cancer cell motility.…”

Section: Discussionsupporting

confidence: 74%

β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells

et al. 2011

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Lung cancer is the leading cause of cancer death worldwide. The epidermal growth factor receptor (EGFR) represents the main target for non-small cell lung cancer (NSCLC) therapy, as its overexpression or constitutive activation contributes to malignancy and correlates with poor prognosis. Our previous work demonstrated that in epithelial cells b1 integrin is required for propagating EGFR signaling from the plasma membrane to the nucleus. In this study, we silenced b1 integrin in human NSCLC A549 cells. The b1 integrin-silenced cells show a defective activation of the EGFR signaling cascade, leading to decreased in vitro proliferation, enhanced sensitivity to cisplatin and Gefitinib, impaired migration and invasive behavior. Inhibitory effects on tumor growth and on the EGFR pathway were also observed in in vivo experiments. Moreover, b1 integrin silencing increases the amount of EGFR on the cell surface, suggesting that b1 integrin is required for efficient constitutive EGFR turnover at the cell membrane. Although the rate of EGF internalization and recycling is not affected in silenced cells, EGFR signaling is recovered only by expression of the Rab-coupling protein RCP, indicating that b1 integrin sustains the endocytic machinery required for EGFR signaling. Overall, these results show that b1 integrin is an essential regulator of EGFR signaling and tumorigenic properties of lung cancer cells, and that its silencing might represent an adjuvant approach to anti-EGFR therapy.

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Section: Discussionsupporting

confidence: 74%

β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells

et al. 2011

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“…Previous work showed that LAMC2 binds to integrin α2/β1, 34 and integrin is required for invasion in some tumors. 35 To test whether integrin participates in LAMC2-induced EMT, we first assessed the potential interaction between LAMC2 and integrin in NSCLC cells. LAMC2 pulldown experiments showed that both endogenous and exogenous LAMC2 interacted with integrin β1 in H2122, PC9, and A549R4 cells (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin β1-and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target. Cell Death and Differentiation (2015) 22, 1341-1352; doi:10.1038/cdd.2014.228; published online 16 January 2015Lung cancer is the leading cause of cancer-related death. 1 Non-small-cell lung cancer (NSCLC) accounts for~80-85% of lung cancers. 2 Only 20-30% of NSCLC are radically resectable and the majority of lung cancer patients succumb to the disease. The high mortality of NSCLC is largely attributable to late diagnosis, when metastases are present. 2 The molecular mechanisms governing metastasis of NSCLC remain poorly understood.Metastasis is a complex, multistep process, involving migration and invasion of malignant cells from the primary tumor to blood vessels, intravasation, and survival in the circulation, and ultimately extravasation, colonization, and formation of secondary tumor at distant target organs. 3 Each of these events is classically driven by the acquisition of genetic and/or epigenetic traits in tumor cells and the cooperation of nonneoplastic stromal cells. Increased or decreased expression of several genes in tumors has been found to be correlated with metastasis. 3 However, specific gene alterations that drive NSCLC metastasis remain largely elusive.Laminin γ2 (LAMC2) is a subunit of the heterotrimeric glycoprotein laminin-332 (LAM-332, formerly laminin-5), consisting of the α3, β3, and γ2 chains. Although LAMC2 is an important structural component of the epithelial basement membrane (BM) in various normal tissues, 4 there is an emerging evidence for a pathological role of LAMC2 monomer in cancer. It has been demonstrated that LAMC2 protein expression correlates with clinical outcome of stage I lung adenocarcinoma (ADC) patients. 5,6 In addition, noncontinuous expression pattern of LAMC2 predicts the prognosis of esophageal squamous cell carcinoma (SCC), 7 and secreted LAMC2 in the serum is associated with the aggressiveness of pancreatic cancer. 8 Besides, LAMC2 monom...

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“…However, b1-integrin-blocking antibodies induced a morphological and functional reversion of tumoral phenotype (Weaver et al, 1997) and blocked the proliferation (Wang et al, 2002) in breast cancer cells. In vulva squamous carcinomas, b1-integrin is overexpressed and required for the invasive pattern (Brockbank et al, 2005). Interestingly, post-transcriptional modification of b1-integrin contributes to colon cancer progression (Seales et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Cooperation between Myc and YY1 provides novel silencing transcriptional targets of α3β1-integrin in tumour cells

et al. 2006

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We show that human osteosarcoma cells (Saos-2) have downregulation of a3b1-integrin compared to normal bone cells; this was further described in human osteosarcomas and in a primary murine sarcoma. The a3 gene was silenced in Saos-2 cells causing a low expression of a3b1-integrin and reduction in collagen attachment with increasing migratory capacity. Chromatin immunoprecipitation assay performed on a3 promoter established that Myc and Yin Yang protein (YY1) cooperate in tandem to downregulate the a3 gene. This silencing mechanism involves the binding of Myc and YY1 to DNA and formation of complexes among Myc/Max, YY1, CREBbinding protein and deacetylation activity. The promoter containing deletions of E-boxes or YY1 cassettes failed to downregulate the transcription of a reporter gene as well as the inhibition of deacetylation activity. Overexpression of both Myc and YY1 was necessary to determine the a3-integrin promoter downregulation in normal osteoblasts. This downregulation of a3b1-integrin can contribute to the acquisition of a more aggressive phenotype. YY1 regulated negatively the Myc activity through a direct interaction with the Myc/Max and deacetylase complexes. This represents a novel silencing mechanism with broad implications in the transcription machinery of tumours.

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Integrin β1 is required for the invasive behaviour but not proliferation of squamous cell carcinoma cells in vivo

Cited by 63 publications

References 38 publications

β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells

β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells

LAMC2 enhances the metastatic potential of lung adenocarcinoma

Cooperation between Myc and YY1 provides novel silencing transcriptional targets of α3β1-integrin in tumour cells

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