The Pivotal Role of Integrin β1 in Metastasis of Head and Neck Squamous Cell Carcinoma

Abstract

Purpose This study aimed to understand the prognostic value of integrin β1 expression in head and neck squamous cell carcinoma (HNSCC) and the mechanism underlying its association with metastatic HNSCC. Experimental Design Archival HNSCC tissues including 99 non-metastatic primary tumors and 101 metastatic primary tumors were examined for the association of integrin β1 expression with metastasis and disease prognosis by appropriate statistical methods. Fluorescence activated cell sorting was used to separate the integrin β1high/+ cell population from the integrin β1low/− population in HNSCC cell lines. These two populations and integrin β1 shRNA knock-down HNSCC cells were examined for the effect of integrin β1 on invasion in vitro and on lymph node and lung metastases in a xenograft mouse model. Expression and activation of matrix metalloproteinases (MMPs) were examined by zymography. Results Statistical analysis showed that integrin β1 expression was significantly higher in the metastatic primary tumors than in the non-metastatic tumors (42.6% vs 24.8%, p<0.0001 and p<0.0001 by univariate and multivariate analyses, respectively). In patients with lymph node metastasis, integrin β1 expression was inversely correlated with overall survival (p=0.035). The integrin β1 knock-down or integrin β1low/− HNSCC cells showed a significant reduction in lymph node and lung metastases in vivo (p<0.001 and p<0.05, respectively). Significantly reduced matrigel invasion capability was also found in integrin β1 knock-down or integrin β1low/− HNSCC cells (p< 0.01). Finally, zymography results showed integrin β1 affected HNSCC invasion by regulating MMP-2 activation. Conclusion These findings indicate that integrin β1 has a major impact on HNSCC prognosis through its regulation of metastasis.

Nitric oxide increases the migratory activity of non-small cell lung cancer cells via AKT-mediated integrin αv and β1 upregulation

“…Accumulating evidence suggests that the motile behavior of cancer cells is accompanied by switches in cellular integrin patterns, with some integrins decreasing and others increasing [20]. Specifically, increases in integrins αv, α5, β1 and β3 have been shown to enhance the migration and metastasis of cancer cells [21][22][23][24].…”

Mechanisms of Invasion in Head and Neck Cancer

“…Although degradation of the ECM, especially the basement membrane, is a key property of invasive tumors, interaction with the ECM is also important for invasion and prognosis. [135][136][137][138] Knockdown of the integrin b1 using short interfering RNA (siRNA) can reduce MMP-2 activity and invasive capability, 139 mimicking the ability of miR-124, which has been shown to target integrin b1 and reduce invasion. 140 The integrin a v b6 is upregulated in wound healing, and inhibition of integrin a v b6 also inhibits invasion.…”

Squamous cell carcinoma of the oral cavity and circulating tumour cells

“…The role of the expression rates of integrin alpha-3 for locoregional and ITGB4 for haematogenous dissemination and, therefore, cancer cell motility and anchorage-independent survival, which are vital for OSCC recurrence and metastasis, has previously been shown. Furthermore, the importance of integrin beta1 in HNSCC and stimulated vascular endothelial growth factor secretion by alphaB-crystallin in HNSCC was specified [100,101] . In addition to these considerations, there might be a spread of tumour-derived molecules on a subcellular level, such as micro-RNAs.…”