Institute of Biochemical Sciences, School of Life Sciences, National Taiwan University, Taipei, Taiwan, ROC.
Anticancer Res. 2010 Oct;30(10):4177-86.
In human tumors, fibronectin (FN) expression is positively associated with tumor metastatic potential and matrix metalloproteinase (MMP) secretion. Additionally, tissue transglutaminase (TG2) is implicated as playing an important role in tumor progression, and acts as a co-receptor for integrin-mediated cell binding to FN. This study explored the involvement of FN and TG2 in cancer cell metastasis using the recently established highly invasive A431-III subline. A431-III cells expressed significantly higher levels of FN and TG2 as compared to the parental line (A431-P). Knockdown of endogenous FN by small interfering RNA (siRNA) resulted in dramatic suppression of the migratory and invasive activity, and the secreted MMP-9 activity (but not MMP-2) in A431-III subline. Exogenous administration of FN to A431-III cells also increased the secreted activity of MMP-9 but not MMP-2. Interestingly, knockdown of TG2 by siRNA dramatically reduced the cell attachment, migration and invasion, and the secretion of MMP-9 and MMP-1 (but not MMP-2 and MMP-3) in A431-III cells as compared to A431-P cells. Furthermore, A431-III cells exhibited increased association of integrin β1 and β3 with FN and TG2, and knockdown of TG2 markedly suppressed integrin β1 interaction with FN. Together, this study suggests that FN and TG2 facilitate the metastatic activity of A431 tumor cells, and this may be partly attributed to TG2 enhancement of the association of FN and β integrin. In addition, the combined targeting of TG2 and FN may be an effective therapeutic strategy for cancer displaying increased expression of both proteins.
在人类肿瘤中，纤维连接蛋白（FN）的表达与肿瘤转移潜能和基质金属蛋白酶（MMP）的分泌呈正相关。此外，组织转谷氨酰胺酶（TG2）被认为在肿瘤进展中发挥重要作用，并作为整合素介导的细胞与 FN 结合的辅助受体。本研究使用最近建立的高侵袭性 A431-III 亚系探讨了 FN 和 TG2 在癌细胞转移中的作用。与亲本系（A431-P）相比，A431-III 细胞表达的 FN 和 TG2 水平明显更高。用小干扰 RNA（siRNA）敲低内源性 FN 导致 A431-III 亚系的迁移和侵袭活性以及分泌的 MMP-9 活性（但不是 MMP-2）显著抑制。外源性给予 FN 也增加了 A431-III 细胞分泌的 MMP-9 活性，但不增加 MMP-2 活性。有趣的是，与 A431-P 细胞相比，用 siRNA 敲低 TG2 显著降低了 A431-III 细胞的细胞黏附、迁移和侵袭以及 MMP-9 和 MMP-1 的分泌（但不是 MMP-2 和 MMP-3）。此外，A431-III 细胞表现出整合素β1 和β3与 FN 和 TG2 的结合增加，而 TG2 的敲低显著抑制了整合素β1 与 FN 的相互作用。总之，本研究表明 FN 和 TG2 促进了 A431 肿瘤细胞的转移活性，这可能部分归因于 TG2 增强了 FN 和β整合素的结合。此外，联合靶向 TG2 和 FN 可能是一种有效的治疗策略，用于治疗同时表达这两种蛋白的癌症。
