Wang Yuanyuan, Zhao Zhi, Zhuang Jing, Wu Xinxin, Wang Zhizhong, Zhang Bing, Gao Ge, Zhang Yinping, Guo Caili, Xia Qingxin
Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou 450008, China.
Department of Pathology, Yihe Hospital, Henan University, No. 69 Agriculture East Road, Zhengzhou 450008, China.
J Cancer. 2021 Apr 20;12(12):3515-3528. doi: 10.7150/jca.51430. eCollection 2021.
Autophagy plays pivotal role in various tumors, including colorectal cancer (CRC). Microsatellite instability (MSI) and mutations are also involved in response to the adjuvant therapy of CRC. We aimed to investigate the relationships among autophagy, mutations, MSI, clinicopathological parameters, and prognosis in CRC patients. We tested 200 CRC tumors for autophagy-related protein expression (Beclin 1 and LC3), MSI status, and mutations. Expression of Beclin 1 and LC3 was higher in CRC, with Beclin 1 significantly correlating with the depth of invasion, whereas LC3 was not associated with clinicopathological parameters. Patients expressing the LC3 proteins experienced a shorter overall survival (OS) after surgery with adjuvant therapy, especially in the MSS/L-CRC subgroup and the mutated subgroup. MSS/L-CRC patients with KRAS mutations positively expressed the LC3 protein and suffered a shorter OS than LC3 non-expressing patients. In CRC patients who received either capecitabine or capecitabine combined with oxaliplatin post-surgery, the positive expression of LC3 correlated with worse OS compared to patients who did not express LC3. Sequencing showed BRCA1/2 as the most variant genes in all patients. Nevertheless, deleterious variations were more frequent in patients with MSI-H CRC. High LC3 protein expression shows a certain prognostic value in CRC patients. LC3, the MSI status, and mutations must be considered when selecting an adjuvant therapy for CRC. The detection of these indexes is of great significance to identify high-risk patients who would benefit from autophagy-related anticancer drugs or help to explore more effective treatment options for patients who are resistant to conventional chemotherapy or relapse.
自噬在包括结直肠癌（CRC）在内的多种肿瘤中发挥着关键作用。微卫星不稳定性（MSI）和基因突变也与CRC的辅助治疗反应有关。我们旨在研究CRC患者中自噬、基因突变、MSI、临床病理参数和预后之间的关系。我们检测了200例CRC肿瘤的自噬相关蛋白表达（Beclin 1和LC3）、MSI状态和基因突变。Beclin 1和LC3在CRC中的表达较高，Beclin 1与浸润深度显著相关，而LC3与临床病理参数无关。表达LC3蛋白的患者在辅助治疗手术后的总生存期（OS）较短，尤其是在微卫星稳定/低错配修复缺陷（MSS/L-CRC）亚组和突变亚组中。KRAS基因突变的MSS/L-CRC患者LC3蛋白呈阳性表达，其OS比不表达LC3的患者短。在术后接受卡培他滨或卡培他滨联合奥沙利铂治疗的CRC患者中，与不表达LC3的患者相比，LC3的阳性表达与较差的OS相关。测序显示BRCA1/2是所有患者中变异最多的基因。然而，有害变异在MSI-H CRC患者中更为常见。LC3蛋白高表达在CRC患者中具有一定的预后价值。在为CRC患者选择辅助治疗时，必须考虑LC3、MSI状态和基因突变。检测这些指标对于识别将从自噬相关抗癌药物中获益的高危患者或帮助探索对传统化疗耐药或复发患者更有效的治疗方案具有重要意义。
