Modulation of tumor cell stiffness and migration by type IV collagen through direct activation of integrin signaling pathway.
Excessive collagen deposition plays a critical role in tumor progression and metastasis. To understand how type IV collagen affects mechanical stiffness and migration, low-collagen-IV-expressing transfectants of B16F10, U118MG, and Huh7 (denoted shCol cells) were established by the lentiviral-mediated delivery of small interfering RNA against type IV-α1 collagen (Col4A1). Although having similar growth rates, shCol cells showed a flatter morphology compared to that of the corresponding controls. Notably, knocking down the Col4A1 gene conferred the cells with higher levels of elasticity and lower motility. Exposure to blocking antibodies against human β1 integrin or α2β1 integrin or the pharmacological inhibition of Src and ERK activity by PP1 and U0126, respectively, effectively reduced cell motility and raised cell stiffness. Reduced Src and ERK activities in shCol cells indicate the involvement of a collagen IV/integrin signaling pathway. The forced expression of β1 integrin significantly stimulated Src and ERK phosphorylation, reduced cell stiffness, and accelerated cell motility. In an experimental metastasis assay using C57BL/6 mice, B16F10 shCol cells formed significantly fewer and smaller lung nodules, confirming the contribution of collagen to metastasis. In summary, the integrin signaling pathway activated in a tumor environment with collagen deposition is responsible for low cell elasticity and high metastatic ability.
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan. Electronic address: wilson1211983@gmail.com.
Sheng-Yi
SY
Chen
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. Electronic address: dutyzoe@gmail.com.
Jo-Shi
JS
Lin
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Center for the Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70101, Taiwan. Electronic address: y1357@mail.ncku.edu.tw.
Bei-Chang
BC
Yang
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D055119:Elastic Modulus; D055785:Gene Knockdown Techniques; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
C547475:COL4A1 protein, human; D024141:Collagen Type IV; D016023:Integrins
Cell stiffness; Col4A1; Integrin; Migration