Open AccessHHLA2 deficiency inhibits non‐small cell lung cancer progression and THP‐1 macrophage M2 polarization
Author(s) -
Sun Wenjie,
Li Shuying,
Tang Guiliang,
Sun Shaoxing,
Luo Yuan,
Bai Rui,
Han Linzhi,
Jiang Xueping,
Gao Yanping,
Huang Zhengrong,
Zhang Junhong,
Gong Yan,
Xie Conghua
Publication year - 2021
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.4081
Subject(s) - cancer research , downregulation and upregulation , cell growth , gene knockdown , lung cancer , mapk/erk pathway , carcinogenesis , macrophage polarization , cell culture , cell cycle , cell , signal transduction , chemistry , medicine , microbiology and biotechnology , biology , cancer , macrophage , in vitro , biochemistry , genetics , gene
Abstract Background Human endogenous retrovirus‐H long terminal repeat‐associating protein 2 (HHLA2) is a member of B7 family, which is upregulated in multiple tumors. However, its exact functions in non‐small cell lung cancer (NSCLC) have not been fully understood. This study aimed to investigate the biological roles of HHLA2 in human NSCLC and the relevant mechanisms. In addition, the effects of tumor cell‐derived HHLA2 on tumor‐associated macrophage (TAM) polarization were explored. Methods NSCLC cell growth, migration, and invasion were assessed by colony formation and modified Boyden chamber assays. Cell cycle and the CD163+ TAMs were examined by flow cytometry. A co‐culture model of THP‐1 macrophages and NSCLC cells was conducted to investigate the impacts of tumor cell‐derived HHLA2 on THP‐1 macrophage polarization. Moreover, a xenograft nude mouse model was established to explore the effects of HHLA2 on tumorigenesis in vivo. Results HHLA2 was upregulated in A549 and H1299 cells compared with the normal lung epithelial BEAS‐2B cells. HHLA2 deficiency inhibited NSCLC cell proliferation, migration, invasion, and induced G0/G1 phase arrest partially via inhibiting EGFR/MAPK/ERK signaling pathway. Furthermore, HHLA2 knockdown inhibited M2 polarization of TAMs via downregulating IL‐10. In addition, knockdown of HHLA2 inhibited tumor growth in vivo. Conclusion HHLA2 downregulation inhibited NSCLC growth and TAM M2 polarization. HHLA2 may serve as a therapeutic target and promising prognostic biomarker in NSCLC.