Non-small-cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common pathological subtype. Epidermal growth factor (EGF) receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR-tyrosine kinase inhibitors (TKIs). The proinflammatory cytokine, interleukin (IL)-17A, and IL-17A-producing cells were reported to be elevated in the tumor microenvironment and peripheral blood of NSCLC patients and to be correlated with tumor progression and poor prognoses. However, the pathophysiological role of IL-17A in NSCLC remains unclear, although some studies suggested its involvement in cancer cell invasion and metastasis. Herein, we observed that expressions of IL-17A and its receptor, IL-17 receptor C (IL-17RC), were elevated in LUAD tissues and were correlated with poor survival in different lung cancer cohorts. In LUAD cells with mutant EGFR, the IL-17A/IL-17RC axis was shown to enhance phosphorylation of EGFR and Met, thereby promoting proliferation and resistance to EGFR-TKIs such as afatinib. In LUAD cells with wild-type (WT) EGFR, we found that the IL-17A/IL-17RC axis enhanced EGF-induced EGFR activation and cell proliferation through causing impairment of EGF-induced EGFR lysosomal degradation. Collectively, our results indicated diverse impacts of the IL-17A/IL-17RC axis on EGFR activation in LUAD cells with WT and mutant EGFR and suggested that developing therapeutic strategies against IL-17A/IL-17RC would be valuable for LUAD treatment.

<p>Supplementary Figures 1-8. Supplementary Figure 1: Stably expressing Keap1 by CL1-5 cells is accompanied by decreasing migratory and invasive abilities. Supplementary Figure 2: Manipulation of Keap1 expression (overexpression or knockdown) had no significant effect on the cell growth rate. Supplementary Figure 3: Keap1 suppresses the mobility of cancer cells. Supplementary Figure 4: Functional confirmation of Keap1 and Nrf2 expressions in CL1-0 and CL1-5 cells. Supplementary Figure 5: Cell proliferation was not affected by Nrf2 or S100P expression. Supplementary Figure 6: Representative IHC images of Nrf2 in lung cancer tissues from surgically resected specimens. Supplementary Figure 7: Keap1 regulates intra-pulmonary metastasis in a CL1-0 xenograft model. Supplementary Figure 8: Keap1 mediates the degradation of RhoA in CL1-5 cells.</p>

<p>Supplementary Tables 1-3. Supplementary Table 1: Clinicopathologic characteristics of patients with associated expression of Keap1 protein in NSCLC. Supplementary Table 2: Correlation between levels of Keap1 and Nrf2 expression in lung cancer. Supplementary Table 3: Clinicopathologic characteristics of lung tumors with high and low expression of Nrf2 protein.</p>

<p>Supplementary Figure legends (Figures 1-8)</p>