Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, China.
Int J Biol Sci. 2021 Apr 12;17(7):1671-1681. doi: 10.7150/ijbs.57964. eCollection 2021.
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 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.
免疫检查点配体程序性死亡配体 1（PD-L1）和跨膜粘蛋白（MUC）3A 在非小细胞肺癌（NSCLC）中上调，导致侵袭性发病机制和预后不良。在这里，我们报告敲低致癌性 MUC3A 可抑制 NSCLC 细胞中 PD-L1 的表达。MUC3A 是表皮生长因子受体（EGFR）稳定性的有效调节剂，MUC3A 缺乏会下调 PI3K/Akt 和 MAPK 通路的激活，从而降低 PD-L1 的表达。此外，敲低 MUC3A 和 EGFR 突变型 NSCLC 细胞中的酪氨酸激酶抑制剂（TKI）对抑制增殖和促进凋亡具有协同作用。在 BALB/c 裸鼠异种移植模型中，MUC3A 缺乏增强了 EGFR 突变型 NSCLC 对 TKI 的敏感性。我们的研究表明，跨膜粘蛋白 MUC3A 诱导 PD-L1，从而促进 NSCLC 中的免疫逃逸，而下调 MUC3A 可增强 EGFR 突变型 NSCLC 中 TKI 的作用。这些发现为 NSCLC 的新型联合治疗方案提供了思路。
