A Novel IGLC2 Gene Linked With Prognosis of Triple-Negative Breast Cancer

Yu-Tien Chang; Wen-Chiuan Tsai; Wei-Zhi Lin; Chia-Chao Wu; Jyh-Cherng Yu; Vincent S Tseng; Guo-Shiou Liao; Je-Ming Hu; Huan-Ming Hsu; Yu-Jia Chang; Meng-Chiung Lin; Chi-Ming Chu; Chien-Yi Yang

doi:10.3389/fonc.2021.759952

A Novel IGLC2 Gene Linked With Prognosis of Triple-Negative Breast Cancer

Front Oncol. 2022 Jan 27:11:759952. doi: 10.3389/fonc.2021.759952. eCollection 2021.

Authors

Yu-Tien Chang¹, Wen-Chiuan Tsai², Wei-Zhi Lin³, Chia-Chao Wu⁴, Jyh-Cherng Yu⁵, Vincent S Tseng⁶, Guo-Shiou Liao⁵, Je-Ming Hu^{7

8

9}, Huan-Ming Hsu^{5

10}, Yu-Jia Chang^{11

12

13}, Meng-Chiung Lin^{14

15}, Chi-Ming Chu^{16

17

18

19}, Chien-Yi Yang¹⁰

Affiliations

¹ School of Public Health, National Defense Medical Center, Taipei, Taiwan.
² Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
³ Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
⁴ Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁵ Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁶ Department of Computer Science, National Chiao Tung University, Hsinchu, Taiwan.
⁷ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
⁸ Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁹ School of Medicine, National Defense Medical Center, Taipei, Taiwan.
¹⁰ Department of Surgery, Songshan Branch of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
¹¹ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹² Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
¹³ Cancer Research Center and Translational Laboratory, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
¹⁴ Division of Gastroenterology, Department of Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan.
¹⁵ Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
¹⁶ Division of Biostatistics and Informatics, Department of Epidemiology, School of Public Health, National Defense Medical Center, Taipei, Taiwan.
¹⁷ Big Data Research Center, Fu-Jen Catholic University, New Taipei City, Taiwan.
¹⁸ Department of Public Health, China Medical University, Taichung, Taiwan.
¹⁹ Department of Healthcare Administration and Medical Informatics College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.

Abstract

Background: Immunoglobulin-related genes are associated with the favorable prognosis of triple-negative breast cancer (TNBC) patients. We aimed to analyze the function and prognostic value of immunoglobulin lambda constant 2 (IGLC2) in TNBC patients.

Methods: We knocked down the gene expression of IGLC2 (IGLC2-KD) in MDA-MB-231 cells to evaluate the proliferation, migration, and invasion of tumors via 3-(4,5-Dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, wound healing, and transwell cell migration assay respectively. Relapse-free survival (RFS) and distant metastasis-free survival (DMFS) analyses were conducted using the KM plotter online tool. The GSE76275 data set was used to analyze the association of IGLC2 and clinical characteristics. A pathway enrichment analysis was conducted using the next-generation sequencing data of wild-type and IGLC2-KD MDA-MB-231 cells.

Results: The low gene expression of IGLC2 was related to unfavorable RFS, DMFS. The high expression of IGLC2 was exhibited in the basal-like immune-activated (BLIA) TNBC molecular subtype, which was immune-activated and showed excellent response to immune therapy. IGLC2 was positively correlated with programmed death-ligand 1 (PD-L1) as shown by Spearman correlation (r = 0.25, p < 0.0001). IGLC2 had a strong prognostic effect on lymph node-negative TNBC (RFS range: 0.31, q value= 8.2e-05; DMFS = 0.16, q value = 8.2e-05) but had no significance on lymph node-positive ones. The shRNA-mediated silencing of IGLC2 increased the proliferation, migration, and invasion of MDA-MB-231 cells. The results of pathway enrichment analysis showed that IGLC2 is related to the PI3K-Akt signaling pathway, MAPK signaling pathway, and extracellular matrix-receptor interaction. We confirmed that MDA-MB-231 tumor cells expressed IGLC2, subverting the traditional finding of generation by immune cells.

Conclusions: IGLC2 linked with the proliferation, migration, and invasion of MDA-MB-231 cells. A high expression of IGLC2 was related to favorable prognosis for TNBC patients. IGLC2 may serve as a biomarker for the identification of TNBC patients who can benefit the most from immune checkpoint blockade treatment.

Keywords: MDA-MB-231; breast cancer; distant metastasis-free survival; immunoglobulin; next-generation sequencing; prognosis; relapse-free survival; triple-negative breast cancer (TNBC).