【佳学基因靶向药物基因检测】抑制结肠癌 K-RasG13D 突变可减少癌细胞增殖，但可通过 RAS/ERK 通路促进干性和炎症

国内大学检测基因公司解释

小组讨论癌症的检测基因解码创新治疗《肿瘤个体治疗的方法与措施》,得知《Front Pharmacol》在 2022 Oct 28;13:996053.发表了一篇题目为《抑制结肠癌 K-RasG13D 突变可减少癌细胞增殖，但可通过 RAS/ERK 通路促进干性和炎症》肿瘤靶向药物治疗基因检测临床研究文章。该研究由Yan Qi, Hong Zou, XiaoHui Zhao, Joanna Kapeleris, Michael Monteiro, Feng Li, Zhi Ping Xu, Yizhen Deng, Yanheng Wu, Ying Tang, Wenyi Gu等完成。促进了肿瘤的正确治疗与个性化用药的发展，进一步强调了基因信息检测与分析的重要性。

肿瘤基因检测及靶向药物治疗研究关键词：

ERK通路, K-RasG13D突变, PI3K/Akt通路,癌症干细胞,结肠癌,肿瘤球体。

肿瘤治疗检测基因临床应用结果

K-Ras 是一种经过充分研究的致癌基因，其突变经常在胰腺癌、肺癌和结直肠癌等上皮癌中发现。由于耐药性和转移特性，携带 K-Ras 突变的癌细胞难以治疗。癌症干细胞 (CSC) 被认为是化疗耐药的主要原因，也是肿瘤反复和转移的原因。但 K-Ras 突变如何影响 CSC 和炎症尚不清楚。在这里，我们比较了两种结肠癌细胞系，HCT-116 和 HT-29，前者是 K-RasG13D 突变体，后者是野生型。我们发现用 K-Ras 突变抑制剂 S7333 处理的 HCT-116 细胞形成的肿瘤球体明显多于未处理的对照，而野生型 HT-29 细胞保持不变。然而，肿瘤球体的大小小于未处理的对照，表明它们的增殖在 S7333 处理后受到抑制。与此一致，干基因Lgr5和CD133的表达显着增加，自我更新基因TGF-β1的表达也增加。流式细胞术分析表明，经处理的 HCT-116 细胞中干细胞表面标志物 CD133 的表达增加。为了解 G13D 突变诱导效应的途径，我们使用特异性抑制剂 SCH772984 和 BEZ235 研究了 RAS/ERK 和 PI3K/Akt 途径。结果表明涉及 RAS/ERK 而不是 PI3K/Akt 通路。由于 CSC 在癌症发展中发挥初始作用，而炎症是肿瘤发生过程中的重要步骤，我们分析了干细胞增加与炎症之间的相关性。我们发现增加的 Lgr5 和 CD133 与促炎因子如 IL-17、IL-22 和 IL-23 密切相关。总之，我们的研究结果表明，K-RasG13D 突变促进癌细胞生长，但降低癌症干性和炎症，从而降低结肠癌的肿瘤发生和转移潜力。抑制这种突变可逆转该过程。因此，在临床上对K-RasG13D突变进行靶向治疗时需要谨慎。关键词：ERK通路； K-RasG13D突变； PI3K/Akt通路；癌症干细胞；结肠癌;炎;肿瘤球体。

肿瘤发生与干预国际数据库描述：

K-Ras is a well-studied oncogene, and its mutation is frequently found in epithelial cancers like pancreas, lung, and colorectal cancers. Cancer cells harboring K-Ras mutations are difficult to treat due to the drug resistance and metastasis properties. Cancer stem cells (CSCs) are believed the major cause of chemotherapeutic resistance and responsible for tumor recurrence and metastasis. But how K-Ras mutation affects CSCs and inflammation is not clear. Here, we compared two colon cancer cell lines, HCT-116 and HT-29, with the former being K-RasG13D mutant and the latter being wildtype. We found that HCT-116 cells treated with a K-Ras mutation inhibitor S7333 formed significantly more tumor spheroids than the untreated control, while the wild type of HT-29 cells remained unchanged. However, the size of tumor spheroids was smaller than the untreated controls, indicating their proliferation was suppressed after S7333 treatment. Consistent with this, the expressions of stem genes Lgr5 and CD133 significantly increased and the expression of self-renewal gene TGF-β1 also increased. The flow cytometry analysis indicated that the expression of stem surface marker CD133 increased in the treated HCT-116 cells. To understand the pathway through which the G13D mutation induced the effects, we studied both RAS/ERK and PI3K/Akt pathways using specific inhibitors SCH772984 and BEZ235. The results indicated that RAS/ERK rather than PI3K/Akt pathway was involved. As CSCs play the initial role in cancer development and the inflammation is a vital step during tumor initiation, we analyzed the correlation between increased stemness and inflammation. We found a close correlation of increased Lgr5 and CD133 with proinflammatory factors like IL-17, IL-22, and IL-23. Together, our findings suggest that K-RasG13D mutation promotes cancer cell growth but decreases cancer stemness and inflammation thus tumorigenesis and metastasis potential in colon cancer. Inhibition of this mutation reverses the process. Therefore, care needs be taken when employing targeted therapies to K-RasG13D mutations in clinics.Keywords: ERK pathway; K-RasG13D mutation; PI3K/Akt pathway; cancer stem cells; colon cancer; inflammation; tumor spheroid.