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LIMK1 nuclear translocation promotes hepatocellular carcinoma progression by increasing p-ERK nuclear shuttling and by activating c-Myc signalling upon EGF stimulation

Oncogene volume 40, pages 2581–2595 (2021)Cite this article

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Abstract

LIM kinase 1 (LIMK1) is a serine/threonine and tyrosine kinase that is predominantly located in the cytoplasm. In our study, nuclear translocation of LIMK1 in clinical hepatocellular carcinoma (HCC) samples was demonstrated for the first time, especially in samples from those with intravascular tumour thrombus. LIMK1 was overexpressed in HCC tissues, and nuclear LIMK1 expression was associated with poor prognosis in HCC patients. Although the effects of cytoplasmic LIMK1 on cofilin phosphorylation and actin filament dynamics have been well studied, the function of nuclear LIMK1 is still unclear. Gain- and loss-of-function experiments were performed both in vitro and in vivo and demonstrated a correlation between nuclear LIMK1 and the enhanced aggressive phenotype of HCC. EGF could drive the nuclear translocation of LIMK1 by activating the interaction of p-ERK and LIMK1 and facilitating their roles in nuclear shuttling. Moreover, nuclear LIMK1 could directly bind to the promoter region of c-Myc and stimulate c-Myc transcription. Although the EGFR monoclonal antibody cetuximab has a poor therapeutic effect on advanced HCC patients, in vivo animal study showed that cetuximab achieved a significant inhibitory effect on the progression of nuclear LIMK1-overexpressing HCC cells. In addition, recent data have demonstrated the potential of cetuximab in combination therapy for HCC patients with LIMK1 nuclear translocation.

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Fig. 1: Nuclear LIMK1 overexpression is associated with the poor prognosis of HCC.
Fig. 2: Nuclear LIMK1 contributes to the aggressive phenotype of HCC cells in vitro.
Fig. 3: LIMK1 and p-ERK interact to facilitate their nuclear translocation.
Fig. 4: Nuclear LIMK1 transcriptionally activates the expression of c-Myc.
Fig. 5: Cetuximab suppresses tumour progression by decreasing the nuclear translocation of LIMK1.
Fig. 6: The schematic diagram demonstrates the mechanism underlying LIMK1 nuclear translocation and the functional mechanism of nuclear LIMK1.

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Acknowledgements

We would like to thank AJE [aje.com] for English language editing.

Author contributions

LZ and RZ led the study design and prepared the manuscript. Z-HP and C-QL carried out the experiments. Y-FZ and Z-YX performed statistical analysis; LW and M-HJ assisted in tissue sample collection. Y-JZ performed data analysis and interpretation.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81773082, 81872423, 81972813, 81702903), Guangdong Natural Science Foundation (2017A030310038, 2018B030311036, 2019A1515010974) and Fork Ying Tung Education Foundation (161035).

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  1. These authors contributed equally: Zhihua Pan, Chaoqun Liu

Authors and Affiliations

  1. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Zhihua Pan, Chaoqun Liu, Yunfei Zhi, Zhiyue Xie, Ling Wu, Muhong Jiang, Yujie Zhang, Rui Zhou & Liang Zhao

  2. Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Zhihua Pan, Chaoqun Liu, Yunfei Zhi, Zhiyue Xie, Ling Wu, Muhong Jiang, Yujie Zhang, Rui Zhou & Liang Zhao

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All experiments performed are endorsed by the Ethics Committee of Southern Medical University and complied with the Declaration of Helsinki. All animal experiments were carried out with the approval of the Southern Medical University Animal Care and Use Committee in accordance with the guidelines for the ethical treatment of animals. All animal experiments involved ethical and humane treatment under a license from the Guangdong Provincial Bureau of Science.

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Pan, Z., Liu, C., Zhi, Y. et al. LIMK1 nuclear translocation promotes hepatocellular carcinoma progression by increasing p-ERK nuclear shuttling and by activating c-Myc signalling upon EGF stimulation. Oncogene 40, 2581–2595 (2021). https://doi.org/10.1038/s41388-021-01736-2

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