Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan, Republic of Korea.
Int J Biochem Cell Biol. 2012 Nov;44(11):2069-76. doi: 10.1016/j.biocel.2012.08.004. Epub 2012 Aug 10.
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.
溶血磷脂酸（LPA）参与体内间充质干细胞刺激肿瘤生长。然而，间充质干细胞促进肿瘤发生的分子机制仍不清楚。在本研究中，我们证明了 A549 人肺腺癌细胞（A549 CM）的条件培养基诱导人脂肪组织来源的间充质干细胞（hASCs）中 ADAM12 的表达，ADAM12 是解整合素和金属蛋白酶家族成员。LPA 受体 1 抑制剂 Ki16425 预处理 hASCs 或用小干扰 RNA 介导的 LPA 受体 1 沉默可阻断 A549 CM 刺激的 ADAM12 表达，表明 LPA-LPA 受体 1 信号轴在 A549 CM 刺激的 ADAM12 表达中起关键作用。用小干扰 RNA 或短发夹 RNA 沉默 ADAM12 表达可阻断 LPA 诱导的 hASCs 中 α-平滑肌肌动蛋白（一种癌相关成纤维细胞的标志物）和 ADAM12 的表达。使用 A549 细胞的异种移植移植模型，我们证明了 ADAM12 的沉默抑制了 hASC 刺激的 A549 异种移植肿瘤的体内生长和移植的 hASC 向 α-平滑肌肌动蛋白阳性癌相关成纤维细胞的分化。hASCs 的 LPA 条件培养基诱导 A549 细胞的黏附，而 ADAM12 的沉默抑制了 LPA 诱导的 hASCs 中细胞外基质蛋白、骨桥蛋白和βig-h3 的表达以及 LPA 条件培养基刺激的 A549 细胞的黏附。这些结果表明，LPA 刺激的 ADAM12 表达在肿瘤生长和 hASC 向表达 α-平滑肌肌动蛋白、骨桥蛋白和βig-h3 的癌相关成纤维细胞分化中起关键作用。
