Yang Yang, Zhang Tao, Wu Lixiang
Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute, Chongqing, 400030, China.
Medical Laboratory, Ankang Central Hospital, No. 85, Jinzhou South Road, Ankang, 725000, Shaanxi, China.
Biochem Genet. 2021 Aug;59(4):1018-1032. doi: 10.1007/s10528-021-10051-0. Epub 2021 Feb 25.
Since the incidence and mortality of colorectal cancer (CRC) are increasing in recent years, the research on the pathogenesis of colorectal cancer has attracted more and more attention. Here, our results confirmed that the mRNA expression level and proteins accumulation of TUFT1 were significantly increased in CRC tissues from late-stage CRC patients (III + IV) (p < 0.001), indicated by qPCR and IHC assay. The TUFT1 expression was positively correlated with tumor stage by analyzing 126 specimens from CRC patients. Next, we found that up-regulation of TUFT1 enhanced the migration and invasion of LoVo cells, whereas the down-regulation of TUFT1 observably weakened the migration and invasion of SW837 cells, indicating that TUFT1 promotes the metastasis of CRC cells. In addition, TUFT1 overexpression increased the number of mammary spheres and vincristine resistance of LoVo cells by sphere formation assay and measuring the IC50 value, suggesting the TUFT1 promotes stemness and the vincristine resistance of CRC cells. Finally, we found that TUFT1 overexpression increased p-AKT in LoVo cells, while down-regulation of TUFT1 decreased the p-AKT levels in SW837 cells. Therefore, we determined that the function of TUFT1 in CRC depends on PI3K/AKT pathway. Taken together, these data demonstrated that TUFI1 facilitates metastasis, stemness, and vincristine resistance of colorectal cancer cells via activation of PI3K/AKT pathway, which might act as a promising therapeutic target for CRC.
近年来，由于结直肠癌（CRC）的发病率和死亡率不断上升，结直肠癌发病机制的研究越来越受到关注。在此，我们的结果证实，通过qPCR和免疫组化分析表明，晚期结直肠癌患者（III + IV期）的CRC组织中TUFT1的mRNA表达水平和蛋白积累显著增加（p < 0.001）。通过分析126例CRC患者的标本，发现TUFT1表达与肿瘤分期呈正相关。接下来，我们发现TUFT1的上调增强了LoVo细胞的迁移和侵袭能力，而TUFT1的下调则明显削弱了SW837细胞的迁移和侵袭能力，这表明TUFT1促进了CRC细胞的转移。此外，通过成球实验和测量IC50值，发现TUFT1过表达增加了LoVo细胞的乳腺球数量和长春新碱耐药性，提示TUFT1促进了CRC细胞的干性和长春新碱耐药性。最后，我们发现TUFT1过表达增加了LoVo细胞中p-AKT的水平，而TUFT1的下调则降低了SW837细胞中p-AKT的水平。因此，我们确定TUFT1在CRC中的功能依赖于PI3K/AKT通路。综上所述，这些数据表明TUFI1通过激活PI3K/AKT通路促进结直肠癌细胞的转移、干性和长春新碱耐药性，这可能是CRC一个有前景的治疗靶点。
