RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:The inflammatory response-related robust machine learning signature in endometrial cancer: Based on multi-cohort studies.
The inflammatory response-related robust machine learning signature in endometrial cancer: Based on multi-cohort studies.
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子宫内膜癌(UCEC)是女性常见癌症,累及子宫内膜。炎症在癌症进展和预后中发挥重要作用,因此识别UCEC中与炎症应答相关的亚型,有助于靶向治疗和个体化医疗。
本研究根据炎症应答相关基因的分子亚型,发现UCEC肿瘤免疫应答存在显著差异。A亚型预后更佳,对抗CTLA-4和抗PDCD1等免疫治疗的应答也更好。功能分析显示各亚型免疫应答存在差异:A亚型中细胞因子信号通路、NK细胞介导细胞毒通路及炎症过程相关基因表达较高,对三种化疗药物的敏感性也更强。
研究发现一个由12个炎症应答相关基因构成的特征,可预测UCEC患者1、2和3年生存。此外,经验证的机器学习特征显示低风险和高风险队列的临床特征存在显著差异。风险评分升高与病理分级较高、年龄较大、分期较晚及免疫亚型C2相关。低风险组CD8+ T细胞和活化CD4+细胞等免疫细胞浸润较多;随着风险评分升高,细胞毒性免疫细胞丰度下降。
最后,研究采用PCR检测P2RX4的差异表达,并发现敲低P2RX4可抑制子宫内膜癌Ishikawa细胞系增殖。总之,该特征可作为临床预测指标,并揭示不同免疫表达模式,有望改善UCEC患者靶向治疗和个体化医疗。
Uterine corpus endometrial carcinoma (UCEC) is a prevalent form of cancer in women, affecting the inner lining of the uterus. Inflammation plays a crucial role in the progression and prognosis of cancer, making it important to identify inflammatory response-related subtypes in UCEC for targeted therapy and personalized medicine.
This study discovered significant variation in immune response within UCEC tumors based on molecular subtypes of inflammatory response-related genes. Subtype A showed a more favorable prognosis and better response to immunotherapies like anti-CTLA4 and anti-PDCD1 therapy.
Functional analysis revealed subtype-specific differences in immune response, with subtype A exhibiting higher expression of genes related to cytokine signaling pathways, NK cell-mediated cytotoxicity pathways and inflammatory processes. Subtype A also showed increased sensitivity to three chemotherapeutic agents. A 12-gene inflammatory response-related signature was found to have prognostic value for 1, 2 and 3 year survival in UCEC patients.
Additionally, a validated machine learning-based signature demonstrated significant differences in clinical traits between low-risk and high-risk cohorts. Elevated risk scores were associated with higher pathological grading, older age, advanced stage and immune subtype C2. Low-risk groups had higher infiltration of immune cell types such as CD8 + T cells and activated CD4 + cells.
However, the abundance of cytotoxic immune cells decreased with increasing risk scores.
Finally, PCR was applied to test the different expression in P2PX4. P2RX4 knockdown inhibited the proliferation and proliferation of the endometrial carcinoma Ishikawa cell line.
In conclusion, this developed signature can serve as a clinical prediction index and reveal distinct immune expression patterns. Ultimately, this study has the potential to enhance targeted therapy and personalized medicine for UCEC patients.
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