Integrated proteogenomic characterization reveals an imbalanced hepatocellular carcinoma microenvironment after incomplete radiofrequency ablation

作者全名："Shi, Zheng-Rong; Duan, Yu-Xin; Cui, Fang; Wu, Zhong-Jun; Li, Mao-Ping; Song, Pei-Pei; Peng, Qi-Ling; Ye, Wen-Tao; Yin, Kun-Li; Kang, Mei-Qing; Yu, Yan-Xi; Yang, Jian; Tang, Wei; Liao, Rui"

作者地址："[Shi, Zheng-Rong; Duan, Yu-Xin; Wu, Zhong-Jun; Ye, Wen-Tao; Yin, Kun-Li; Kang, Mei-Qing; Yu, Yan-Xi; Yang, Jian; Liao, Rui] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Youyi Rd, Chongqing 400016, Peoples R China; [Cui, Fang] Chongqing Med Univ, Dept Lab Med, Affiliated Hosp 1, Chongqing, Peoples R China; [Li, Mao-Ping] Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 1, Chongqing, Peoples R China; [Song, Pei-Pei; Tang, Wei] Natl Ctr Global Hlth & Med, Tokyo, Japan; [Peng, Qi-Ling] Chongqing Med Univ, Fac Basic Med Sci, Chongqing 400016, Peoples R China"

通信作者："Liao, R (通讯作者)，Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Youyi Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000995375500001

JCR分区：Q1

影响因子：11.4

年份：2023

卷号：42

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Liver cancer; Thermal ablation; Omics analysis; Immune response; Proteinase 3

摘要："Background Efforts to precisely assess tumor-specific T-cell immune responses still face major challenges, and the potential molecular mechanisms mediating hepatocellular carcinoma (HCC) microenvironment imbalance after incomplete radiofrequency ablation (iRFA) are unclear. This study aimed to provide further insight into the integrated transcriptomic and proteogenomic landscape and identify a new target involved in HCC progression following iRFA. Methods Peripheral blood and matched tissue samples were collected from 10 RFA-treated HCC patients. Multiplex immunostaining and flow cytometry were used to assess local and systemic immune responses. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were explored via transcriptomic and proteogenomic analyses. Proteinase-3 (PRTN3) was identified in these analyses. And then, the ability of PRTN3 to predict overall survival (OS) was assessed in 70 HCC patients with early recurrence after RFA. In vitro CCK-8, wound healing and transwell assays were conducted to observe interactions between Kupffer cells (KCs) and HCC cells induced by PRTN3. The protein levels of multiple oncogenic factors and signaling pathway components were detected by western blotting. A xenograft mouse model was built to observe the tumorigenic effect of PRTN3 overexpression on HCC. Results Multiplex immunostaining revealed no immediate significant change in local immune cell counts in periablational tumor tissues after 30 min of iRFA. Flow cytometry showed significantly increased levels of -CD4(+) T cells, -CD4(+)CD8(+) T cells, and -CD4(+)CD25(+)CD127- Tregs and significantly decreased the levels of -CD16(+)CD56(+) natural killer cells on day 5 after cRFA (p < 0.05). Transcriptomics and proteomics revealed 389 DEGs and 20 DEPs. Pathway analysis showed that the DEP-DEGs were mainly enriched in the immunoinflammatory response, cancer progression and metabolic processes. Among the DEP-DEGs, PRTN3 was persistently upregulated and closely associated with the OS of patients with early recurrent HCC following RFA. PRTN3 expressed in KCs may affect the migration and invasion of heat stress-treated HCC cells. PRTN3 promotes tumor growth via multiple oncogenic factors and the PI3K/AKT and P38/ERK signaling pathways. Conclusions This study provides a comprehensive overview of the immune response and transcriptomic and proteogenomic landscapes of the HCC milieu induced by iRFA, revealing that PRTN3 promotes HCC progression after iRFA."

基金机构："National Natural Science Foundation of China [82170666]; Japan China Sasakawa Medical Fellowship (44th); Natural Science Foundation of Chongqing [CSTB2022NSCQ-MSX0112)]; Science and Health Joint Research Project of Chongqing Municipality [2020GDRC013]; Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0087]"

基金资助正文："This research was supported by the National Natural Science Foundation of China (No. 82170666); Japan China Sasakawa Medical Fellowship (44th); Natural Science Foundation of Chongqing (No. CSTB2022NSCQ-MSX0112); Science and Health Joint Research Project of Chongqing Municipality (2020GDRC013); Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0087)."