【佳學(xué)基因靶向藥物基因檢測】抑制結(jié)腸癌 K-RasG13D 突變可減少癌細(xì)胞增殖，但可通過 RAS/ERK 通路促進干性和炎癥

國內(nèi)大學(xué)檢測基因公司解釋

小組討論癌癥的檢測基因解碼創(chuàng)新治療《腫瘤個體治療的方法與措施》,得知《Front Pharmacol》在 2022 Oct 28;13:996053.發(fā)表了一篇題目為《抑制結(jié)腸癌 K-RasG13D 突變可減少癌細(xì)胞增殖，但可通過 RAS/ERK 通路促進干性和炎癥》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由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。促進了腫瘤的正確治療與個性化用藥的發(fā)展，進一步強調(diào)了基因信息檢測與分析的重要性。

腫瘤基因檢測及靶向藥物治療研究關(guān)鍵詞：

ERK通路, K-RasG13D突變, PI3K/Akt通路,癌癥干細(xì)胞,結(jié)腸癌,腫瘤球體。

腫瘤治療檢測基因臨床應(yīng)用結(jié)果

K-Ras 是一種經(jīng)過充分研究的致癌基因，其突變經(jīng)常在胰腺癌、肺癌和結(jié)直腸癌等上皮癌中發(fā)現(xiàn)。由于耐藥性和轉(zhuǎn)移特性，攜帶 K-Ras 突變的癌細(xì)胞難以治療。癌癥干細(xì)胞 (CSC) 被認(rèn)為是化療耐藥的主要原因，也是腫瘤反復(fù)和轉(zhuǎn)移的原因。但 K-Ras 突變?nèi)绾斡绊?CSC 和炎癥尚不清楚。在這里，我們比較了兩種結(jié)腸癌細(xì)胞系，HCT-116 和 HT-29，前者是 K-RasG13D 突變體，后者是野生型。我們發(fā)現(xiàn)用 K-Ras 突變抑制劑 S7333 處理的 HCT-116 細(xì)胞形成的腫瘤球體明顯多于未處理的對照，而野生型 HT-29 細(xì)胞保持不變。然而，腫瘤球體的大小小于未處理的對照，表明它們的增殖在 S7333 處理后受到抑制。與此一致，干基因Lgr5和CD133的表達顯著增加，自我更新基因TGF-β1的表達也增加。流式細(xì)胞術(shù)分析表明，經(jīng)處理的 HCT-116 細(xì)胞中干細(xì)胞表面標(biāo)志物 CD133 的表達增加。為了解 G13D 突變誘導(dǎo)效應(yīng)的途徑，我們使用特異性抑制劑 SCH772984 和 BEZ235 研究了 RAS/ERK 和 PI3K/Akt 途徑。結(jié)果表明涉及 RAS/ERK 而不是 PI3K/Akt 通路。由于 CSC 在癌癥發(fā)展中發(fā)揮初始作用，而炎癥是腫瘤發(fā)生過程中的重要步驟，我們分析了干細(xì)胞增加與炎癥之間的相關(guān)性。我們發(fā)現(xiàn)增加的 Lgr5 和 CD133 與促炎因子如 IL-17、IL-22 和 IL-23 密切相關(guān)?？傊?，我們的研究結(jié)果表明，K-RasG13D 突變促進癌細(xì)胞生長，但降低癌癥干性和炎癥，從而降低結(jié)腸癌的腫瘤發(fā)生和轉(zhuǎn)移潛力。抑制這種突變可逆轉(zhuǎn)該過程。因此，在臨床上對K-RasG13D突變進行靶向治療時需要謹(jǐn)慎。關(guān)鍵詞：ERK通路； K-RasG13D突變； PI3K/Akt通路；癌癥干細(xì)胞；結(jié)腸癌;炎;腫瘤球體。

腫瘤發(fā)生與干預(yù)國際數(shù)據(jù)庫描述：

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.

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