LncRNA-HOXC-AS2 regulates tumor-associated macrophage polarization through the STAT1/SOCS1 and STAT1/CIITA pathways to promote the progression of non-small cell lung cancer

Cunli Yin; Jing Li; Siru Li; Xi Yang; Yingchun Lu; Chunyu Wang; Bin Liu

doi:10.1016/j.cellsig.2023.111031

LncRNA-HOXC-AS2 regulates tumor-associated macrophage polarization through the STAT1/SOCS1 and STAT1/CIITA pathways to promote the progression of non-small cell lung cancer

Cell Signal. 2024 Mar:115:111031. doi: 10.1016/j.cellsig.2023.111031. Epub 2023 Dec 31.

Authors

Cunli Yin¹, Jing Li², Siru Li¹, Xi Yang³, Yingchun Lu¹, Chunyu Wang³, Bin Liu⁴

Affiliations

¹ School of Medicine, University of Electronic Science and Technology of China, China.
² Department of General Internal Medicine, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China Chengdu, China.
³ School of Medicine and Life Sciences, Chengdu University of Traditional Chinese Medicine, China.
⁴ Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China Chengdu, China. Electronic address: binliu202003@126.com.

PMID: 38168631
DOI: 10.1016/j.cellsig.2023.111031

Abstract

Tumor-associated macrophages (TAMs) mainly exhibit the characteristics of M2-type macrophages, and the regulation of TAM polarization is a new target for cancer therapy, among which lncRNAs are key regulatory molecules. This study aimed to explore the effects of lncRNA-HOXC-AS2 on non-small cell lung cancer (NSCLC) by regulating TAM polarization. THP-1 cells were used to differentiate into macrophages, and TAMs were obtained by coculture with A549 cells. The M1/M2 cell phenotype and HOXC-AS2 expression were detected, and A549-derived exosomes (A549-exo) were used to elucidate the effects of A549 on macrophage polarization and HOXC-AS2 expression. Then, by interfering with HOXC-AS2 or STAT1, the effects of HOXC-AS2 regulation of STAT1 on the TAM phenotype and STAT1/SOCS1 and STAT1/CIITA pathways were analyzed, and the proliferation and metastasis of NSCLC cells in the coculture system were also detected. Results showed that HOXC-AS2 expression in M2 macrophages and TAMs was significantly higher than that in M1 macrophages, and A549-exo promoted HOXC-AS2 expression and M2 polarization. Intervention HOXC-AS2 resulted in increased M1 marker expression, decreased M2 marker expression, and activation of STAT1/SOCS1 and STAT1/CIITA pathways in TAMs. In addition, HOXC-AS2 was mainly expressed in the cytoplasm of TAMs and could bind to STAT1. Further experiments confirmed that intervention HOXC-AS2 promoted the M1 polarization of TAMs by targeting STAT1 and weakened the promoting effects of TAMs on the proliferation and metastasis of NSCLC. In conclusion, HOXC-AS2 inhibited the activation of STAT1/SOCS1 and STAT1/CIITA pathways and promoted M2 polarization of TAMs by binding with STAT1, thus promoting NSCLC.

Keywords: Non-small cell lung cancer; Polarization; STAT1/SOCS1 and STAT1/CIITA pathways; Tumor-associated macrophage; lncRNA-HOXC-AS2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Non-Small-Cell Lung* / metabolism
Cell Line, Tumor
Humans
Lung Neoplasms* / metabolism
Macrophages / metabolism
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
STAT1 Transcription Factor / metabolism
Suppressor of Cytokine Signaling 1 Protein / genetics
Suppressor of Cytokine Signaling 1 Protein / metabolism
Tumor Microenvironment
Tumor-Associated Macrophages / metabolism

Substances

RNA, Long Noncoding
SOCS1 protein, human
Suppressor of Cytokine Signaling 1 Protein
STAT1 protein, human
STAT1 Transcription Factor