Medical Research Center for Ischemic Tissue Regeneration, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 626-870, Korea.
Exp Mol Med. 2010 Apr 30;42(4):280-93. doi: 10.3858/emm.2010.42.4.027.
Lysophosphatidic acid (LPA) stimulates growth and invasion of ovarian cancer cells and tumor angiogenesis. Cancer-derived LPA induces differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) to alpha-smooth muscle actin (alpha-SMA)-positive cancer-associated fibroblasts. Presently, we explored whether cancer-derived LPA regulates secretion of pro-angiogenic factors from hASCs. Conditioned medium (CM) from the OVCAR-3 and SKOV3 ovarian cancer cell lines stimulated secretion angiogenic factors such as stromal-derived factor-1 alpha (SDF-1 alpha) and VEGF from hASCs. Pretreatment with the LPA receptor inhibitor Ki16425 or short hairpin RNA lentiviral silencing of the LPA((1)) receptor abrogated the cancer CM-stimulated expression of alpha-SMA, SDF-1, and VEGF from hASCs. LPA induced expression of myocardin and myocardin-related transcription factor-A, transcription factors involved in smooth muscle differentiation, in hASCs. siRNA-mediated depletion of endogenous myocardin and MRTF-A abrogated the expression of alpha-SMA, but not SDF-1 and VEGF. LPA activated RhoA in hASCs and pretreatment with the Rho kinase inhibitor Y27632 completely abrogated the LPA-induced expression of alpha-SMA, SDF-1, and VEGF in hASCs. Moreover, LPA-induced alpha-SMA expression was abrogated by treatment with the ERK inhibitor U0126 or the phosphoinositide-3-kinase inhibitor LY294002, but not the PLC inhibitor U73122. LPA-induced VEGF secretion was inhibited by LY294002, whereas LPA-induced SDF-1 secretion was markedly attenuated by U0126, U73122, and LY294002. These results suggest that cancer-secreted LPA induces differentiation of hASCs to cancer-associated fibroblasts through multiple signaling pathways involving Rho kinase, ERK, PLC, and phosphoinositide-3-kinase.
溶血磷脂酸（LPA）刺激卵巢癌细胞的生长和侵袭，并促进肿瘤血管生成。源自癌症的 LPA 可诱导人脂肪组织来源的间充质干细胞（hASCs）分化为α-平滑肌肌动蛋白（α-SMA）阳性的癌相关成纤维细胞。目前，我们探讨了源自癌症的 LPA 是否调节 hASC 分泌促血管生成因子。OVCAR-3 和 SKOV3 卵巢癌细胞系的条件培养基（CM）可刺激 hASC 分泌基质衍生因子-1α（SDF-1α）和 VEGF 等血管生成因子。LPA 受体抑制剂 Ki16425 预处理或 LPA1 受体短发夹 RNA 慢病毒沉默可阻断癌症 CM 刺激的 hASC 中 α-SMA、SDF-1 和 VEGF 的表达。LPA 诱导 hASC 中心肌调节蛋白和心肌调节蛋白相关转录因子-A 的表达，这两种转录因子均参与平滑肌分化。内源性心肌调节蛋白和 MRTF-A 的 siRNA 耗竭可阻断 α-SMA 的表达，但不阻断 SDF-1 和 VEGF 的表达。LPA 可激活 hASCs 中的 RhoA，Rho 激酶抑制剂 Y27632 预处理可完全阻断 LPA 诱导的 hASC 中 α-SMA、SDF-1 和 VEGF 的表达。此外，ERK 抑制剂 U0126 或磷酸肌醇 3-激酶抑制剂 LY294002 可阻断 LPA 诱导的 α-SMA 表达，但 PLC 抑制剂 U73122 则不能阻断 LPA 诱导的 α-SMA 表达。LY294002 抑制 LPA 诱导的 VEGF 分泌，但 U0126、U73122 和 LY294002 则显著抑制 LPA 诱导的 SDF-1 分泌。这些结果表明，源自癌症的 LPA 通过涉及 Rho 激酶、ERK、PLC 和磷酸肌醇 3-激酶的多种信号通路诱导 hASC 分化为癌相关成纤维细胞。
