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Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy

Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy

Authors :
Bufu Tang
Jinyu Zhu
Yueli Shi
Yajie Wang
Xiaojie Zhang
Biao Chen
Shiji Fang
Yang Yang
Liyun Zheng
Rongfang Qiu
Qiaoyou Weng
Min Xu
Zhongwei Zhao
Jianfei Tu
Minjiang Chen
Jiansong Ji
Source :
Molecular Cancer, Vol 23, Iss 1, Pp 1-23 (2024)
Publication Year :
2024
Publisher :
BMC, 2024.

Abstract

Abstract Background The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. Methods Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification–mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. Results We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). Conclusions Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.

Details

Language :
English
ISSN :
14764598
Volume :
23
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Molecular Cancer
Publication Type :
Academic Journal
Accession number :
edsdoj.b8f52a172445cc97cf8aba7c34db9b
Document Type :
article
Full Text :
https://doi.org/10.1186/s12943-024-02049-0