Int J Biol Sci 2021; 17(7):1671-1681. doi:10.7150/ijbs.57964
MUC3A induces PD-L1 and reduces tyrosine kinase inhibitors effects in EGFR-mutant non-small cell lung cancer
1. Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.
2. Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, China.
3. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.
4. Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China.
5. Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
* These authors contributed equally to this work.
Luo Y, Ma S, Sun Y, Peng S, Zeng Z, Han L, Li S, Sun W, Xu J, Tian X, Wang F, Wu Q, Xiao Y, Zhang J, Gong Y, Xie C. MUC3A induces PD-L1 and reduces tyrosine kinase inhibitors effects in EGFR-mutant non-small cell lung cancer. Int J Biol Sci 2021; 17(7):1671-1681. doi:10.7150/ijbs.57964. Available from https://www.ijbs.com/v17p1671.htm
The immune checkpoint ligand programmed death-ligand 1 (PD-L1) and the transmembrane mucin (MUC) 3A are upregulated in non-small cell lung cancer (NSCLC), contributing to the aggressive pathogenesis and poor prognosis. Here, we report that knocking down the oncogenic MUC3A suppresses the PD-L1 expression in NSCLC cells. MUC3A is a potent regulator of epidermal growth factor receptor (EGFR) stability, and MUC3A deficiency downregulates the activation of the PI3K/Akt and MAPK pathways, which subsequently reduces the expression of PD-L1. Furthermore, knockdown of MUC3A and tyrosine kinase inhibitors (TKIs) in EGFR-mutant NSCLC cells play a synergistic effect on inhibited proliferation and promoted apoptosis in vitro. In the BALB/c nude mice xenograft model, MUC3A deficiency enhances EGFR-mutated NSCLC sensitivity to TKIs. Our study shows that transmembrane mucin MUC3A induces PD-L1, thereby promoting immune escape in NSCLC, while downregulation of MUC3A enhances TKIs effects in EGFR-mutant NSCLC. These findings offer insights into the design of novel combination treatment for NSCLC.
Keywords: MUC3A, non-small cell lung cancer, EGFR, PD-L1.