PDF(Pubmed)
Abstract：
Objective: Tumor necrosis factor (TNF) receptor type II (TNFR2) is expressed by a wide spectrum of tumor cells including colon cancer, non-Hodgkin lymphoma, myeloma, renal carcinoma and ovarian cancer, and its exact role remains to be fully understood. In this study, we examined the effect of genetic ablation of TNFR2 on in vitro and in vivo growth of mouse MC38 and CT26 colon cancer cells. Methods: CRISPR/Cas9 technology was used to knockout TNFR2 on mouse MC38 and CT26 colon cancer cells. In vitro growth and colony formation of wild-type (W.T.) and TNFR2 deficiency of MC38 and CT26 cells, as well as the potential mechanism, was studied. The growth of W.T. and TNFR2 deficient MC38 and CT26 tumors in mice and intratumoral CD8 CTLs were also examined. Results: TNFR2 deficiency impaired in vitro proliferation and colony formation of cancer cells. This was associated with the inhibition of protein kinase B (AKT) phosphorylation and enhanced autophagy-induced cell death. Moreover, deficiency of TNFR2 also markedly impaired in vivo growth of MC38 or CT26 in the syngeneic C57BL/6 mice or BALB/c mice, respectively, accompanied by the decrease in soluble TNFR2 levels in the circulation and the increase in the number of tumor-infiltrating IFNγ+ CD8 cells. Conclusion: TNFR2 plays a role in the growth of mouse colon cancers. Our study provides further experimental evidence to support the development of TNFR2 antagonistic agents in the treatment of cancer.
摘要：
目的:肿瘤坏死因子(TNF)受体Ⅱ型(TNFR2)在包括结肠癌在内的多种肿瘤细胞中表达,非霍奇金淋巴瘤,骨髓瘤,肾癌和卵巢癌，其确切作用仍有待充分理解。在这项研究中,我们研究了TNFR2基因消融对小鼠MC38和CT26结肠癌细胞体外和体内生长的影响。方法:采用CRISPR/Cas9技术敲除小鼠MC38和CT26结肠癌细胞的TNFR2。野生型（W.T.）和TNFR2缺乏的MC38和CT26细胞的体外生长和集落形成，以及潜在的机制，被研究过。还检查了小鼠中W.T.和TNFR2缺陷型MC38和CT26肿瘤的生长以及肿瘤内CD8CTL。结果：TNFR2缺乏对癌细胞的体外增殖和集落形成有损害。这与抑制蛋白激酶B（AKT）磷酸化和增强自噬诱导的细胞死亡有关。此外，在同基因C57BL/6小鼠或BALB/c小鼠中，TNFR2的缺乏也显著损害MC38或CT26的体内生长，分别,伴随着循环中可溶性TNFR2水平的降低和肿瘤浸润性IFNγ+CD8细胞数量的增加。结论：TNFR2在小鼠结肠癌的生长过程中起一定作用。我们的研究提供了进一步的实验证据来支持TNFR2拮抗剂在癌症治疗中的发展。
