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Journal of Cancer Research and Clinical Oncology

Erschienen in:

30.10.2023 | Research

Components of the JNK–MAPK pathway play distinct roles in hepatocellular carcinoma

verfasst von: Jijun Yu, Xinying Li, Junxia Cao, Ting Zhu, Shuifeng Liang, Le Du, Meng Cao, Haitao Wang, Yaolin Zhang, Yinxi Zhou, Beifen Shen, Jiannan Feng, Jiyan Zhang, Jing Wang, Jianfeng Jin

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 19/2023

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Abstract

Purpose

Mitogen-activated protein kinases (MAPK), specifically the c-Jun N-terminal kinase (JNK)–MAPK subfamily, play a crucial role in the development of various cancers, including hepatocellular carcinoma (HCC). However, the specific roles of JNK1/2 and their upstream regulators, MKK4/7, in HCC carcinogenesis remain unclear.

Methods

In this study, we performed differential expression analysis of JNK–MAPK components at both the transcriptome and protein levels using TCGA and HPA databases. We utilized Kaplan–Meier survival plots and receiver operating characteristic (ROC) curve analysis to evaluate the prognostic performance of a risk scoring model based on these components in the TCGA-HCC cohort. Additionally, we conducted immunoblotting, apoptosis analysis with FACS and soft agar assays to investigate the response of JNK–MAPK pathway components to various death stimuli (TRAIL, TNF-α, anisomycin, and etoposide) in HCC cell lines.

Results

JNK1/2 and MKK7 levels were significantly upregulated in HCC samples compared to paracarcinoma tissues, whereas MKK4 was downregulated. ROC analyses suggested that JNK2 and MKK7 may serve as suitable diagnostic genes for HCC, and high JNK2 expression correlated with significantly poorer overall survival. Knockdown of JNK1 enhanced TRAIL-induced apoptosis in hepatoma cells, while JNK2 knockdown reduced TNF-α/cycloheximide (CHX)—and anisomycin-induced apoptosis. Neither JNK1 nor JNK2 knockdown affected etoposide-induced apoptosis. Furthermore, MKK7 knockdown augmented TNF-α/CHX- and TRAIL-induced apoptosis and inhibited colony formation in hepatoma cells.

Conclusion

Targeting MKK7, rather than JNK1/2 or MKK4, may be a promising therapeutic strategy to inhibit the JNK–MAPK pathway in HCC therapy.

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Titel: Components of the JNK–MAPK pathway play distinct roles in hepatocellular carcinoma
verfasst von: Jijun Yu
Xinying Li
Junxia Cao
Ting Zhu
Shuifeng Liang
Le Du
Meng Cao
Haitao Wang
Yaolin Zhang
Yinxi Zhou
Beifen Shen
Jiannan Feng
Jiyan Zhang
Jing Wang
Jianfeng Jin
Publikationsdatum: 30.10.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 19/2023
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-023-05473-9

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Components of the JNK–MAPK pathway play distinct roles in hepatocellular carcinoma