LINC00665 interacts with BACH1 to activate Wnt1 and mediates the M2 polarization of tumor-associated macrophages in GC

Bo Yang; Kun Su; Guanyu Sha; Qingqing Bai; Gengxin Sun; Huidong Chen; Hongmei Xie; Xuan Jiang

doi:10.1016/j.molimm.2022.03.120

LINC00665 interacts with BACH1 to activate Wnt1 and mediates the M2 polarization of tumor-associated macrophages in GC

Mol Immunol. 2022 Jun:146:1-8. doi: 10.1016/j.molimm.2022.03.120. Epub 2022 Apr 5.

Authors

Bo Yang¹, Kun Su¹, Guanyu Sha², Qingqing Bai¹, Gengxin Sun¹, Huidong Chen¹, Hongmei Xie¹, Xuan Jiang³

Affiliations

¹ Department of Oncology, Suqian Hospital of Traditional Chinese Medicine, Su qian, Jiang su, China.
² Radiation Treatment Center, Suqian Hospital Affiliated to Xuzhou Medical University, Su qian, Jiang su, China.
³ Department of Oncology, Huai'an Second People's Hospital, Affiliated to Xuzhou Medical University, Huai an, Jiang su, China. Electronic address: chip163@163.com.

PMID: 35395473
DOI: 10.1016/j.molimm.2022.03.120

Abstract

Gastric cancer (GC) remains one of the prevalent causes of cancer-related deaths globally. Long non-coding RNAs (lncRNAs) have been associated with different cancers. The polarization of macrophages towards the M2 (alternatively activated) phenotype promotes immunologic tolerance and can induce gastric tumorigenesis. Thus far, lncRNAs have been shown to modulate the differentiation of immune cells. Here, we investigated the biological effects of LINC00665 on the progression of GC and explored the mechanisms underlying its ability to mediate the polarization of macrophages towards the M2 phenotype. We report that the levels of LINC00665 were increased in GC tissues. Furthermore, this increase in LINC00665 expression could be associated with decreased overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS). Using cell-based macrophage polarization models, we demonstrated that LINC00665 upregulation in GC cells facilitated the polarization of macrophages towards the M2 but not M1 (classically activated) phenotype. Furthermore, the loss of LINC00665 prevented the M2 polarization of macrophages. Mechanically, we identified that Wnt1 was the downstream target of LINC00665. Additionally, LINC00665 could directly interact with the transcription factor BTB domain and CNC homology 1 (BACH1). The interaction between LINC00665 and BACH1 resulted in the activation and binding of BACH1 to the Wnt1 promoters. Furthermore, BACH1 silencing could inhibit GC progression, which highlighted a crucial role for BACH1 in LINC00665-mediated Wnt1 activation. In addition, genetic Wnt1 overexpression effectively abolished the repression of Wnt signaling after BACH1 depletion and mediated GC development by supporting M2 macrophage polarization. In conclusion, we report that LINC00665 modulates M2 macrophage polarization and suggest that it may facilitate macrophage-dependent GC progression.

Keywords: BACH1; LINC00665; M2 macrophage polarization; Wnt1.

MeSH terms

Basic-Leucine Zipper Transcription Factors* / genetics
Humans
Macrophage Activation
RNA, Long Noncoding* / genetics
Stomach Neoplasms* / metabolism
Tumor-Associated Macrophages* / cytology
Wnt1 Protein

Substances

BACH1 protein, human
Basic-Leucine Zipper Transcription Factors
RNA, Long Noncoding
WNT1 protein, human
Wnt1 Protein