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Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma

Title
Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma
Authors
Chen, YulongTerajima, MasahikoYang, YananSun, LiAhn, Young-HoPankova, DanielaPuperi, Daniel S.Watanabe, TakeshiKim, Min P.Blackmon, Shanda H.Rodriguez, JaimeLiu, HuiBehrens, CarmenWistuba, Ignacio I.Minelli, RosalbaScott, Kenneth L.Sanchez-Adams, JohannahGuilak, FarshidPati, DebanandaThilaganathan, NishanBurns, Alan R.Creighton, Chad J.Martinez, Elisabeth D.Zal, TomaszGrande-Allen, K. JaneYamauchi, MitsuoKurie, Jonathan M.
Ewha Authors
안영호
SCOPUS Author ID
안영호scopus
Issue Date
2015
Journal Title
JOURNAL OF CLINICAL INVESTIGATION
ISSN
0021-9738JCR Link1558-8238JCR Link
Citation
vol. 125, no. 3, pp. 1147 - 1162
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Indexed
SCI; SCIE; SCOPUS WOS
Abstract
Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. However, the biochemical nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen cross-links. Utilizing resected human lung cancer tissues and a p21(CIP1/WAF1)-deficient, K-ras(G12D)-expressing murine metastatic lung cancer model, we showed that, relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde-derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde-derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Gain- and loss-of-function studies in tumor cells showed that lysyl hydroxylase 2 (LH2), which hydroxylates telopeptidyl lysine residues on collagen, shifted the tumor stroma toward a high-HLCC, low-LCC state, increased tumor stiffness, and enhanced tumor cell invasion and metastasis. Together, our data indicate that LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma.
DOI
10.1172/JCI74725
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의학전문대학원 > 의학과 > Journal papers
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