Pumilio1 regulates NPM3/NPM1 axis to promote PD-L1-mediated immune escape in gastric cancer

作者全名："Wang, Han; Zhou, Zhijun; Zhang, Junchang; Hao, Tengfei; Wang, Pengliang; Wu, Pei; Su, Rishun; Yang, Huan; Deng, Guofei; Chen, Songyao; Gu, Liang; He, Yulong; Zeng, Leli; Zhang, Changhua; Yin, Songcheng"

作者地址："[Wang, Han; Zhang, Junchang; Hao, Tengfei; Su, Rishun; Yang, Huan; Deng, Guofei; Chen, Songyao; Gu, Liang; He, Yulong; Zeng, Leli; Zhang, Changhua; Yin, Songcheng] Sun Yat Sen Univ, Affiliated Hosp 7, Digest Dis Ctr, Guangdong Prov Key Lab Digest Canc Res, Shenzhen, Guangdong, Peoples R China; [Wang, Han] Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, Dept Gastrointestinal Surg, Guangzhou, Guangdong, Peoples R China; [Zhou, Zhijun] Univ Oklahoma Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA; [Zhang, Junchang] Jinan Univ, Dept Metab & Bariatr Surg, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China; [Wang, Pengliang] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Gastrointestinal Surg, Guangzhou, Guangdong, Peoples R China; [Wu, Pei] Chongqing Med Univ, Dept Gastrointestinal Surg, Yongchuan Hosp, Chongqing, Peoples R China; [He, Yulong] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Gastrointestinal Surg, Guangzhou, Guangdong, Peoples R China"

通信作者："He, YL; Zeng, LL; Zhang, CH; Yin, SC (通讯作者)，Sun Yat Sen Univ, Affiliated Hosp 7, Digest Dis Ctr, Guangdong Prov Key Lab Digest Canc Res, Shenzhen, Guangdong, Peoples R China."

来源：CANCER LETTERS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001127865900001

JCR分区：Q1

影响因子：9.7

年份：2024

卷号：581

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Gastric cancer; PUM1; PD-L1; NPM3; Immune escape

摘要："Abnormal regulation of RNA binding proteins (RBPs) plays an essential role in tumorigenesis and progression, but their functions and mechanisms remain largely elusive. Previously, we reported that Pumilio 1 (PUM1), a RBP, could regulate glycolysis metabolism and promote the progression of gastric cancer (GC). However, the role of PUM1 in tumor immune regulation remains largely elusive. In this study, we report that PUM1 induces im-mune escape through posttranscriptional regulation of PD-L1 in GC. We used multiplexed immunohistochemistry to analyze the correlation between PUM1 expression and immune microenvironment in GC. The effect of PUM1 deficiency on tumor killing of T cells was examined in vitro and in vivo. The molecular mechanism of PUM1 was evaluated via RNA immunoprecipitation, chromatin immunoprecipitation, Western blot, co-immunoprecipitation, and RNA stability assays. Clinically, elevated PUM1 expression is associated with high-expression of PD-L1, lack of CD8+ T cell infiltration and poor prognosis in GC patients. PUM1 positively regu-lates PD-L1 expression and PUM1 reduction enhances T cell killing of tumors. Mechanistically, PUM1 directly binds to nucleophosmin/nucleoplasmin 3 (NPM3) mRNA and stabilizes NPM3. NPM3 interacts with NPM1 to promote NPM1 translocation into the nucleus and increase the transcription of PD-L1. PUM1 inhibits the anti -tumor activity of T cells through the PUM1/NPM3/PD-L1 axis. In summary, this study reveals the critical post-transcriptional effect of PUM1 in the modulation of PD-L1-dependent GC immune escape, thus provides a novel indicator and potential therapeutic target for cancer immunotherapy."

基金机构："National Natural Science Foundation of China [82003104, 82073148, 81772579]; Natural Science Foundation of Shenzhen [JCYJ20220530145012027]; Guangdong Provincial Key Laboratory of Digestive Cancer Research [2021B1212040006]; Sanming Project of Medicine in Shenzhen [SZSM201612022]; Fundamental Research Funds for the Central Universities [21623303]; Shenzhen Sustainable Project [KCXFZ202002011010593]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (82003104, 82073148, and 81772579) , Natural Science Foundation of Shenzhen (JCYJ20220530145012027) , Guangdong Provincial Key Laboratory of Digestive Cancer Research (2021B1212040006) , Sanming Project of Medicine in Shenzhen (SZSM201612022) , Fundamental Research Funds for the Central Universities (21623303) , and Shenzhen Sustainable Project (KCXFZ202002011010593) . All these study sponsors have no roles in the study design, in the collection, analysis and interpretation of data."