Protocadherin 10 suppresses tumorigenesis and metastasis in colorectal cancer and its genetic loss predicts adverse prognosis
Protocadherin 10 suppresses tumorigenesis and metastasis in colorectal cancer and its genetic loss predicts adverse prognosis
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DOI：
10.1002/ijc.28899
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发表时间：
2014-12-01
影响因子：
6.4
通讯作者：
Yang, Ya-Chien
中科院分区：
文献类型：
--
作者：
Jao, Tzu-Ming;Tsai, Ming-Hong;Yang, Ya-Chien
原钙粘蛋白 10 (PCDH10) 是人类癌症中的一种新型肿瘤抑制基因，位于结直肠癌 (CRC) 染色体 4q28 的常见缺失区域。本研究旨在确定PCDH10的遗传缺失及其在结直肠癌中的临床相关性，并探讨PCDH10的抑癌功能。通过杂合性丢失研究，在171对原发性肿瘤和相应的正常粘膜中确定了PCDH10的基因缺失。总共有 53 个癌症的 PCDH10 等位基因缺失呈阳性。遗传畸变与肿瘤进展和远处转移显着相关（分别为 p=0.021 和 p=0.018），并且是 CRC 患者生存不良的独立预测因子（p=0.005）。与匹配的正常粘膜相比，在所有测试的 12 个 CRC 细胞系中以及 53 个结直肠癌中的 41 个中，PCDH10 基因的表达均被沉默或显着下调。 PCDH10 的异位表达在体外抑制癌细胞增殖、不依赖锚定的生长、迁移和侵袭。将表达 PCDH10 的 CRC 细胞皮下注射到 SCID 小鼠体内，发现与模拟接种的小鼠相比，肿瘤生长减少。此外，通过脾内植入，沉默细胞中 PCDH10 的重新表达抑制了 SCID 小鼠的肝转移并提高了存活率。总之，PCDH10是结直肠癌中关键的抑癌基因，其功能的丧失不仅会促进肿瘤进展，还会促进肝转移。此外，PCDH10 的基因缺失是 CRC 患者生存的不良预后标志。
Protocadherin 10 (PCDH10), a novel tumor suppressor gene in human cancers, is located in a common deleted region at chromosome 4q28 in colorectal cancer (CRC). This study aimed to ascertain the genetic loss of PCDH10 and its clinical relevance in CRC and to explore the tumor suppressor function of PCDH10. The genetic deletion of PCDH10 was determined in 171 pairs of primary tumors and corresponding normal mucosae by loss of heterozygosity study. In total, 53 carcinomas were positive for allelic loss of PCDH10. The genetic aberration was significantly associated with tumor progression and distant metastasis (p=0.021 and p=0.018, respectively) and was an independent predictor of poor survival for CRC patients (p=0.005). Expression of PCDH10 gene was silenced or markedly down-regulated in all of 12 CRC cell lines tested and in 41 of 53 colorectal carcinomas compared with their matched normal mucosae. Ectopic expression of PCDH10 suppressed cancer cell proliferation, anchorage-independent growth, migration and invasion in vitro. Subcutaneous injection of PCDH10-expressing CRC cells into SCID mice revealed the reduction of tumor growth compared with that observed in mock-inoculated mice. Furthermore, through intrasplenic implantation, the re-expression of PCDH10 in silenced cells restrained liver metastasis and improved survival in SCID mice. In conclusion, PCDH10 is a pivotal tumor suppressor in CRC, and the loss of its function promotes not only tumor progression but also liver metastasis. In addition, the genetic deletion of PCDH10 represents an adverse prognostic marker for the survival of patients with CRC.