Growth Factor-Independent 1 Is a Tumor Suppressor Gene in Colorectal Cancer
Growth Factor-Independent 1 Is a Tumor Suppressor Gene in Colorectal Cancer
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DOI：
10.1158/1541-7786.mcr-18-0666
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发表时间：
2019-03-01
影响因子：
5.2
通讯作者：
Shroyer, Noah F.
中科院分区：
文献类型：
--
作者：
Chen, Min-Shan;Lo, Yuan-Hung;Shroyer, Noah F.
结直肠癌是美国第三大常见癌症，也是导致癌症死亡的第三大原因。生长因子独立1 （Growth factor-independent 1, GFI1）是一种锌指转录抑制因子，负责控制小肠和结肠的分泌细胞分化。GFI1在包括白血病、肺癌和前列腺癌在内的人类恶性肿瘤的发展中起着重要作用。然而，GFI1在结直肠癌进展中的作用在很大程度上是未知的。我们的研究结果表明，GFI1的RNA和蛋白表达在晚期非黏液性结直肠癌中降低。皮下肿瘤异种移植模型表明，在4种不同的人类结直肠癌细胞系中重新表达GFI1可抑制肿瘤生长。为了进一步研究Gfi1在新生结直肠肿瘤发生中的作用，我们培育了由CDX2-cre驱动的结肠中Gfi1缺失的转基因小鼠（Gfi1F/F; CDX2-cre），并将其与Apc（Min/+）小鼠(Apc(Min/+)；Gfi1F / F;CDX2-cre)。与APC突变的对照组相比，Gfi1缺失显著增加了结直肠腺瘤的总数。此外，我们发现化合物(Apc(Min/+)；Gfi1F / F;CDX2-cre)小鼠会出现更大的腺瘤、浸润性癌以及表达神经内分泌标志物嗜铬粒蛋白A的增生性病变，这一特征此前在小鼠apc突变肿瘤中未被描述。总的来说，这些结果表明GFI1在结直肠癌中作为肿瘤抑制基因，其中GFI1的缺乏促进结肠恶性肿瘤。意义：这些发现揭示了gfi1在结直肠肿瘤发生中作为肿瘤抑制基因发挥作用。
Colorectal cancer is the third most common cancer and the third leading cause of cancer death in the United States. Growth factor-independent 1 (GFI1) is a zinc finger transcriptional repressor responsible for controlling secretory cell differentiation in the small intestine and colon. GFI1 plays a significant role in the development of human malignancies, including leukemia, lung cancer, and prostate cancer. However, the role of GFI1 in colorectal cancer progression is largely unknown. Our results demonstrate that RNA and protein expression of GFI1 are reduced in advanced-stage nonmucinous colorectal cancer. Subcutaneous tumor xenograft models demonstrated that the reexpression of GFI1 in 4 different human colorectal cancer cell lines inhibits tumor growth. To further investigate the role of Gfi1 in de novo colorectal tumorigenesis, we developed transgenic mice harboring a deletion of Gfi1 in the colon driven by CDX2-cre (Gfi1F/F; CDX2-cre) and crossed them with Apc(Min/+) mice (Apc(Min/+); Gfi1F/F; CDX2-cre). Loss of Gfi1 significantly increased the total number of colorectal adenomas compared with littermate controls with an APC mutation alone. Furthermore, we found that compound (Apc(Min/+); Gfi1F/F; CDX2-cre) mice develop larger adenomas, invasive carcinoma, as well as hyperplastic lesions expressing the neuroendocrine marker chromogranin A, a feature that has not been previously described in APC-mutant tumors in mice. Collectively, these results demonstrate that GFI1 acts as a tumor suppressor gene in colorectal cancer, where deficiency of Gfi1 promotes malignancy in the colon.Implications: These findings reveal that GFI1functions as a tumor suppressor gene in colorectal tumorigenesis.