OPG is regulated by β-catenin and mediates resistance to TRAIL-induced apoptosis in colon cancer
OPG is regulated by β-catenin and mediates resistance to TRAIL-induced apoptosis in colon cancer
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DOI：
10.1158/1078-0432.ccr-07-5019
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发表时间：
2008-08-01
影响因子：
11.5
通讯作者：
Kolligs, Frank T.
中科院分区：
文献类型：
--
作者：
De Toni, Enrico N.;Thieme, Susanne E.;Kolligs, Frank T.
目的：细胞凋亡抵抗是肿瘤的一个标志，与肿瘤的侵袭性和预后不良密切相关。Wnt/β-catenin通路在结直肠癌的发生中起关键作用，其机制尚未完全阐明。以前的研究已经将骨保护素(OPG)的调节与Wnt/β-catenin信号联系起来。由于OPG也是肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的诱饵受体，我们推测OPG可能在介导结直肠癌细胞的凋亡抵抗中发挥作用。实验设计：人结直肠癌细胞株的表达分析和功能研究，以及结直肠癌患者原发肿瘤和血清中表达的测定。结果：我们发现结直肠癌细胞中OPG的产生受β-连环蛋白/Tcf-4的调节。在结直肠癌细胞中加入外源性OPG可产生对TRAIL的耐药性。同样，培养细胞培养上清液中积累的OPG导致对TRAIL的抗性，这种情况可以通过去除OPG来逆转。结论：Wnt/β-catenin通路可能通过驱动OPG的表达而参与肿瘤的发生和癌细胞的生存。生存因子OPG的表达可能为结直肠癌细胞提供必要的生长优势，促进细胞的侵袭和转移。抑制OPG的表达可能为治疗OPG高表达的结直肠癌患者提供新的治疗途径，并使这些肿瘤对TRAIL诱导的细胞凋亡敏感。
Purpose: Resistance to apoptosis is a hallmark of cancer and correlates with aggressiveness of tumors and poor prognosis. The Wnt/beta-catenin pathway plays a pivotal role in the genesis of colorectal cancer by mechanisms not fully elucidated yet. Previous studies have linked regulation of osteoprotegerin (OPG) in bone to Wnt/beta-catenin signaling. As OPG also serves as a decoy receptor for tumor necrosis factor-related a poptosis-inducing ligand (TRAIL), we hypothesized that OPG might play a role in mediating resistance to apoptosis in colorectal cancer cells.Experimental Design: Expression analysis and functional studies in human colorectal cancer cell lines and determination of expression in primary tumors and sera from patients with colorectal cancer.Results: We found production of OPG in colorectal cancer cells to be regulated by beta-catenin/Tcf-4. Addition of exogenous OPG to colorectal cancer cells caused resistance to TRAIL. Similarly, accumulation of OPG in medium of cultivated cells caused resistance to TRAIL, and this could be reverted by removal of OPG. Furthermore, OPG levels were significantly increased in serum of patients with advanced disease.Conclusions: We conclude that the Wnt/beta-catenin pathway contributes to carcinogenesis and cancer cell survival by driving expression of OPG. Expression of the survival factor OPG might provide colorectal cancer cells with an essential growth advantage and contribute to cell invasion and metastasis. Inhibition of OPG expression might offer a new therapeutic approach for the treatment of patients with colorectal tumors over-expressing OPG and make these tumors sensitive to TRAIL-induced apoptosis.