title: Stimulation of TLR4 by LMW-HA induces metastasis in human papillary thyroid carcinoma through CXCR7.
abstract: In inflammatory sites, high molecular weight hyaluronan fragments are degraded into lower molecular weight hyaluronan fragments (LMW-HA) to regulate immune responses. However, the function of LMW-HA in PTC progression remains to be elucidated. In this study, we found that receptor of LMW-HA, TLR4, was aberrantly overexpressed in PTC tissues and cell line W3. Exposure of W3 cells to LMW-HA promoted cell proliferation and migration via TLR4. Knockdown of TLR4 has provided evidence that TLR4 is essential for LMW-HA-induced CXCR7 expression, which is responsible for LMW-HA-induced proliferation and migration of W3 cells. In tumor-bearing adult nude mice, stimulation of LMW-HA on W3 cells promotes CXCR7 expression in tumor masses (P = 0.002) and tumor growth (P < 0.001). To further confirm our findings, we investigated the clinicopathologic significance of TLR4 and CXCR7 expression using immumohistochemistry in 135 human PTC tissues and 56 normal thyroid tissue samples. Higher rates of TLR4 (53%) and CXCR7 (24%) expression were found in PTC tissues than in normal tissues. Expression of TLR4 or CXCR7 is associated with tumor size and lymph node metastasis. Therefore, LMW-HA may contribute to the development of PTC via TLR4/CXCR7 pathway, which may be a novel target for PTC immunomodulatory therapy.
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine (SJTUSM), 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Shipeng
authors.initials: S
authors.lastname: Dang
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated First People's Hospital, 100 Haining Road, Shanghai 200080, China.
authors.forename: Yongde
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Endocrinology and Metabolism, Ruijin Hospital, SJTUSM, 197 Ruijin 2nd Road, Shanghai 200025, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ye
authors.affiliation: Shanghai Institute of Immunology, Institutes of Medical Sciences, SJTUSM, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Bengbu Medical College and Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu 233004, China.
authors.forename: Zhongqing
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Bengbu Medical College and Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu 233004, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Bengbu Medical College and Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu 233004, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Bengbu Medical College and Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu 233004, China.
authors.forename: Yunzhi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Bengbu Medical College and Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu 233004, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cancer Hospital, HeFei Institutes of Physical Science, Chinese Academy of Science, 350 Shushan Lake Road, HeFei 230031, China.
authors.forename: Xiyan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine (SJTUSM), 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine (SJTUSM), 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Yiji
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Shanghai Institute of Immunology, Institutes of Medical Sciences, SJTUSM, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Nie
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine (SJTUSM), 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated First People's Hospital, 100 Haining Road, Shanghai 200080, China ; Shanghai Institute of Immunology, Institutes of Medical Sciences, SJTUSM, 280 South Chongqing Road, Shanghai 200025, China ; Department of Endocrinology and Metabolism, The First Affiliated Hospital of Bengbu Medical College and Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu 233004, China.
authors.forename: Huanbai
authors.initials: H
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008875:Middle Aged; D008970:Molecular Weight; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: C501896:ACKR3 protein, human; D054387:Receptors, CXCR; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid