Lysophosphatidic acid-induced ADAM12 expression mediates human adipose tissue-derived mesenchymal stem cell-stimulated tumor growth.
Lysophosphatidic acid (LPA) is involved in mesenchymal stem cell-stimulated tumor growth in vivo. However, the molecular mechanism by which mesenchymal stem cells promote tumorigenesis remains elusive. In the present study, we demonstrate that conditioned medium from A549 human lung adenocarcinoma cells (A549 CM) induced the expression of ADAM12, a disintegrin and metalloproteases family member, in human adipose tissue-derived mesenchymal stem cells (hASCs). A549 CM-stimulated ADAM12 expression was abrogated by pretreatment of hASCs with the LPA receptor 1 inhibitor Ki16425 or by small interfering RNA-mediated silencing of LPA receptor 1, suggesting a key role for the LPA-LPA receptor 1 signaling axis in A549 CM-stimulated ADAM12 expression. Silencing of ADAM12 expression using small interfering RNA or short hairpin RNA abrogated LPA-induced expression of both α-smooth muscle actin, a marker of carcinoma-associated fibroblasts, and ADAM12 in hASCs. Using a xenograft transplantation model of A549 cells, we demonstrated that silencing of ADAM12 inhibited the hASC-stimulated in vivo growth of A549 xenograft tumors and the differentiation of transplanted hASCs to α-smooth muscle actin-positive carcinoma-associated fibroblasts. LPA-conditioned medium from hASCs induced the adhesion of A549 cells and silencing of ADAM12 inhibited LPA-induced expression of extracellular matrix proteins, periostin and βig-h3, in hASCs and LPA-conditioned medium-stimulated adhesion of A549 cells. These results suggest a pivotal role for LPA-stimulated ADAM12 expression in tumor growth and the differentiation of hASCs to carcinoma-associated fibroblasts expressing α-smooth muscle actin, periostin, and βig-h3.
Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan, Republic of Korea.
Eun Kyoung
EK
Do
Young Mi
YM
Kim
Soon Chul
SC
Heo
Yang Woo
YW
Kwon
Sang Hun
SH
Shin
Dong-Soo
DS
Suh
Ki-Hyung
KH
Kim
Man-Soo
MS
Yoon
Jae Ho
JH
Kim
D051722:ADAM Proteins / Q000378:metabolism*; D000072199:ADAM12 Protein; D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099222:betaIG-H3 Protein
D051722:ADAM Proteins; D000072199:ADAM12 Protein; D000199:Actins; D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D008246:Lysophospholipids; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C541116:ACTA2 protein, human; C512835:POSTN protein, human; C000606480:ADAM12 protein, human; C032881:lysophosphatidic acid