Oral cancer is amongst the top three cancers in India [1], [2]. Almost 90 % of the oral cancers are identified as squamous cell carcinomas (SCC) [3]. Recent reports from the global cancer observatory show that the number of new cases of lip and oral cavity cancer in 2020 was 377,713 whereas the 5-year prevalence rate in Asian population is 60.9 % (Global cancer observatory survey, December 2020). Despite advancements in treatment protocols, the 5-year survival rates of oral cancer have been extremely low for several decades [4], thereby demanding the need to develop alternative treatment regimen. Toward this, previous studies have reported the contribution of the tumor inflammatory environment in cancer progression and metastasis. The cells in the tumor inflammatory state release various cytokines and chemokines favorable to the tumor progression and growth [5]. Targeting the bioactive molecules exuded from the tumor microenvironment can help in development of alternative targeted therapeutic approaches for management of cancer. In this regard, interleukin-6 (IL-6) and interleukin-8 (IL-8) are the major pro-inflammatory molecules commonly seen upregulated in cancerous and inflamed tissues and their production is controlled by a nuclear-factor (NFκB), which is activated in inflammation and cancer [6], [7], [8]. Till date, IL-8, has been studied for targeting various hallmarks in different types of cancers. As an example, IL-8 and its receptor CXCR2 mediated pathway modulation inhibited the proliferation of chemoresistant colorectal cancer cells HCT116 via stimulation of IL-1α and its receptor [9]. Further, blockade of IL-8/IL-8R axis reduced mesenchymal features of erlotinib resistant lung cancer cells and increased its sensitivity towards erlotinib by modulating p38 MAPK [10]. Chemotherapy induced IL-8 secretion also enhances the ABCB1/ MDR1 expression in tumor endothelial cells conferring drug resistance; targeting this can be a novel strategy in cancer drug resistance [11]. In another study, blockade of IL-8 with antibody demonstrated antitumor effects in cervical cancer growth and metastasis [12], In yet another study, IL-8 was demonstrated to promote ovarian cancer cell migration by induction of EMT [13]. Wang et al showed that blockade of IL-8 receptor using Reparixin/ Repertaxin inhibited malignant behavior of human gastric cancer cells via Akt/ERK signaling [14]. Although IL-8 has been demonstrated as a novel target in different types of cancers, its role t in OSCC remains largely unexplored. IL-8 has been known as a response modulator in Bevacizumab-based preclinical trials in HNSCC [15]. Further, it has shown to promote proliferation and migration in squamous cell carcinoma [16], and cancer progression via CXCR1/2, Akt/ERK-NFκB pathways [17], [18]. However, the mechanistic insight into the role of IL-8 on epithelial-to-mesenchymal transition (EMT) and chemoresistance in OSCC is still at its infancy.

In the present study, we demonstrate interleukin-8 (IL-8) as a target molecule in oral cancer and the effect of blocking exogenous IL-8 on tumor metastasis and chemoresistance in SCC131 and SCC131R (cisplatin resistant subline) cells. Blockade of exogenous IL-8 resulted in decreased EMT, migration and invasion in SCC131 cells and increased apoptosis in SCC131R cells. On the other hand, restoring exogenous IL-8 increased EMT, migration and invasion in SCC131 cells as well as increased chemoresistance via upregulated ABCB1 transporter. Mechanistic investigation further revealed that recombinant IL-8 (rIL-8) treatment activated the Akt/ERK pathway while treatment with neutralizing-IL-8 antibody (nIL-8 Ab) blocked Akt/ERK pathway. We hypothesis that IL-8 activated IκB and p65 subunits of NFκB which helped in nuclear translocation of the p65 subunit and hence overexpression of ABCB1 and chemoresistance [19]. To the best of our knowledge, this is the first study that provides mechanistic insights into the role of IL-8 in modulating metastasis and chemoresistance in OSCC.