HSF4 promotes tumor progression of colorectal cancer by transactivating c-MET
HSF4 promotes tumor progression of colorectal cancer by transactivating c-MET
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HSF4通过反式激活c-MET促进结直肠癌的肿瘤进展
DOI：
10.1007/s11010-022-04582-2
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发表时间：
2022-10
影响因子：
4.3
通讯作者：
Yu Zhang
中科院分区：
文献类型：
--
作者：
Wenjing Zhang;Xuelian Zhang;Peng Cheng;Kelin Yue;Ming Tang;Yan Li;Qiang Guo;Yu Zhang
热休克因子(HSFs)是一个转录因子家族，由HSF1、HSF2和HSF4组成，调节细胞的应激反应，以维持细胞对不利刺激的稳态。最近的研究揭示了HSF1和HSF2在包括结直肠癌(CRC)在内的肿瘤发展中的调控作用。然而，与先天性白内障的病理密切相关的HSF4在肿瘤中的研究仍然较少。在这项研究中，我们旨在描述HSF4在结直肠癌进展中的调节作用和潜在的分子机制。通过对TCGA数据库的生物信息学分析和TMA-IHC分析，我们发现HSF4在大肠癌组织中的表达较正常结肠组织显著上调，是结直肠癌患者预后不良的一个预后因素。功能检测，包括CCK-8、集落形成、Transwell实验和异种移植小鼠模型，证实HSF4促进细胞生长、集落形成、体外侵袭和体内肿瘤生长是一种潜在的致癌因子。机制上，染色质免疫沉淀(ChIP)和免疫印迹分析结果表明，HSF4直接与MET启动子结合，增强c-Met的表达，从而促进下游ERK1/2和AKT信号通路的活性。在进一步的挽救实验中，c-met表达的恢复消除了HSF4表达下调所引起的抑制细胞生长和侵袭。综上所述，我们的研究结果描述了HSF4通过增强c-Met及其下游ERK1/2和AKT信号通路的活性在CRC进展中的关键作用，并强调HSF4是抗CRC治疗的潜在治疗靶点。
Heat shock factors (HSFs) are a family of transcription factors, composed of HSF1, HSF2, and HSF4, to regulate cell stress reaction for maintaining cellular homeostasis in response to adverse stimuli. Recent studies have disclosed the roles of HSF1 and HSF2 in modulating tumor development, including colorectal cancer (CRC). However, HSF4, which is closely associated with pathology of congenital cataracts, remains less studied in tumors. In this study, we aimed to describe the regulatory effects of HSF4 and underlying molecular mechanism in CRC progression. By bioinformatic analysis of TCGA database and TMA-IHC assay, we identified that the expression of HSF4 was significantly upregulated in CRCs compared with normal colonic tissues and was a prognostic factor of poor outcomes of CRC patients. Function assays, including CCK-8, colony formation, transwell assays, and xenografted mouse model, were employed to verify that HSF4 promoted cell growth, colony formation, invasion of CRC cells in vitro, and tumor growth in vivo as a potential oncogenic factor. Mechanistically, results of Chromatin immunoprecipitation (ChIP) and immunoblotting assays revealed that HSF4 associated directly toMETpromoter to enhance expression of c-MET, a well-known oncogene in multiple cancers, thus fueling the activity of downstream ERK1/2 and AKT signaling pathways. In further rescue experiments, restoration of c-MET expression abolished inhibitory cell growth and invasion induced by downregulated HSF4 expression. To sum up, our findings describe a crucial role of HSF4 in CRC progression by enhancing activity of c-MET and downstream ERK1/2 and AKT signaling pathways, and highlight HSF4 as a potential therapeutic target for anti-CRC treatment.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
HSF1作为癌症生物标志物和治疗靶标。
影响因子：
3
作者：
Carpenter RL;Gökmen-Polar Y
通讯作者：
Gökmen-Polar Y
影响因子：
8
作者：
Björk JK;Åkerfelt M;Joutsen J;Puustinen MC;Cheng F;Sistonen L;Nees M
通讯作者：
Nees M
DOI：
--
发表时间：
1995-02
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
M. D. Renzo;M. Olivero;A. Giacomini;H. Porte;E. Chastre;L. Mirossay;B. Nordlinger;S. Bretti-S.-Bret
通讯作者：
M. D. Renzo;M. Olivero;A. Giacomini;H. Porte;E. Chastre;L. Mirossay;B. Nordlinger;S. Bretti-S.-Bret
影响因子：
6.7
作者：
Ma, Peng;Tang, Wei-Guo;Yu, Kai-Huan
通讯作者：
Yu, Kai-Huan