Serglycin in tumor microenvironment promotes non-small cell lung cancer aggressiveness in a CD44-dependent manner.
Tumor microenvironment (TME) plays an active role in promoting tumor progression. To further understand the communication between TME and tumor cells, this study aimed at investigating the involvement of CD44, a type I cell surface receptor, in the crosstalk between tumor cells and TME. We have previously shown that chondroitin sulfate proteoglycan serglycin (SRGN), a CD44-interacting factor, was preferentially secreted by cancer-associated fibroblasts (CAFs) for promoting tumor growth in breast cancer patients. In this study, we show that SRGN is overexpressed in primary non-small cell lung cancers (NSCLCs), by both carcinoma and stromal cells. Using gain-of-function and loss-of-function approaches, we show that SRGN promotes NSCLC cell migration and invasion as well as colonization in the lung and liver in a CD44-dependent manner. SRGN induces lung cancer cell stemness, as demonstrated by its ability to enhance NSCLC cell sphere formation via Nanog induction, accompanied with increased chemoresistance and anoikis-resistance. SRGN promotes epithelial-mesenchymal transition by enhancing vimentin expression via CD44/NF-κB/claudin-1 (CLDN1) axis. In support, CLDN1 and SRGN expression are tightly linked together in primary NSCLC. Most importantly, increased expression of SRGN and/or CLDN1 predicts poor prognosis in primary lung adenocarcinomas. In summary, we demonstrate that SRGN secreted by tumor cells and stromal components in the TME promotes malignant phenotypes through interacting with tumor cell receptor CD44, suggesting that a combined therapy targeting both CD44 and its ligands in the TME may be an attractive approach for cancer therapy.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
J-Y
JY
Guo
Department of Thoracic Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
H-S
HS
Hsu
Department of Biotechnology, Chia Nan University of Pharmacy & Science, Tainan, Taiwan.
S-W
SW
Tyan
Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan.
F-Y
FY
Li
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
J-Y
JY
Shew
Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Institute of Clinical Medicine, China Medical University, Taichung, Taiwan.
W-H
WH
Lee
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
J-Y
JY
Chen
D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D062445:Claudin-1 / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism*; D016019:Survival Analysis; D059016:Tumor Microenvironment; D033921:Vesicular Transport Proteins / Q000378:metabolism*
D062445:Claudin-1; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D011509:Proteoglycans; D033921:Vesicular Transport Proteins; C075430:serglycin