Lung cancer is one of the most frequent cancers worldwide, being categorized as small cell carcinoma or non-small cell carcinoma (NSCLC), and shows 2.2 million new cases (11.4 % of total cancer cases) and 1.8 million deaths (18.0 % of total cancer deaths) reported by GLOBOCAN 2020 [1]. NSCLC, which accounts for approximately 85 % of lung cancer cases, leads a considerable disease burden and appears to be influenced by stage of disease. Despite advances in understanding of the disease pathogenesis, risk, progression and treatment options for NSCLC, it remains the leading cause of cancer death in some regions [2,3]. Among the cancer death-associated factors, distant metastasis is the primary cause and involved in a multi-step process. Nevertheless, the underlying molecular mechanisms involved in lung cancer metastases and tumor markers for predicting the risk of aggressive tumor metastasis are still elusive [[4], [5], [6]]. Therefore, it is urgent to perform in-depth exploration on the pathogenesis of NSCLC, reveal certain novel target molecules associated with distant metastasis, develop precision medicine, and even construct efficacy monitoring or prognosis prediction.

It is well known that the occurrence and development of tumors are regulated by multiple factors, among which the tumor microenvironment serves as a key factor [7,8]. The tumor microenvironment is comprised of cellular and non-cellular components, and presents characteristics of hypoxia, acidification, malnutrition, vascular proliferation and so on [9]. Notably, complex signal pathway network of tumor microenvironment plays an essential role in promoting and inhibiting growth of malignant tumors depending on the circumstances [[10], [11], [12]]. Accumulating evidences indicated that acidity of tumor microenvironment is associated with the migration and invasion of several malignant tumors, and our previous studies had observed similar effects in NSCLC [13,14]. However, relevant molecular mechanisms of acidic microenvironment involved in this process are not fully understood and it deserves to be studied further.

Integrin β6 (ITGB6), as a members of integrin family with epithelial specificity, has been reported to be highly expressed in multiple tumor types and is positively correlated with tumor metastasis and disease progression [[15], [16], [17]]. In our previous studies, we found that acidic microenvironment could induce increased expression of ITGB6 in NSCLC cells, suggesting that this gene might play an important role in the occurrence and development of lung cancer [14]. However, the upstream and downstream regulatory mechanisms associated with ITGB6 in lung cancer have not been fully clarified and need to be further elucidated.

This current study aimed to explore the interaction between acidic microenvironment and ITGB6, and further elucidate the underlying molecular mechanisms in lung cancer. Ultimately, we identified acidity-induced ITGB6 as a molecule that mediate upstream ETS proto-oncogene 1 (ETS1) and downstream epithelial-mesenchymal transition (EMT) and focal adhesion to regulate the metastasis of lung cancer cells. These results might provide new insights into a novel mechanism of an acidity-induced ITGB6 axis in progression of NSCLC, which offers new candidate targets to be exploited for diagnostic and therapeutic strategies.