LIMK1 promotes peritoneal metastasis of gastric cancer and is a therapeutic target

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Abstract

Peritoneal metastasis is a common form of metastasis among advanced gastric cancer patients. In this study, we reported the identification of LIM domain kinase 1 (LIMK1) as a promoter of gastric cancer peritoneal metastasis, and its potential to be a therapeutic target of dabrafenib (DAB). Using transcriptomic sequencing of paired gastric cancer peritoneal metastasis, primary tumors, and normal gastric tissues, we first unveiled that LIMK1 is selectively up-regulated in metastatic tumors. Increased LIMK1 in gastric cancer peritoneal metastasis was validated by immunohistochemistry analysis of an independent patient cohort. In vitro functional studies demonstrated that LIMK1 knockout or knockdown significantly inhibited cell migration and invasion of gastric cancer cells. LIMK1 knockout also abrogated peritoneal and liver metastases of gastric cancer cells in nude mice in vivo. Dabrafenib, a small molecule targeting LIMK1, was found to decrease cell migration and invasion of gastric cancer cells in vitro and abolish peritoneal and liver metastasis formation in vivo. Mechanistically, either LIMK1 knockout or Dabrafenib inhibited LIMK1 expression and phosphorylation of its downstream target cofilin. Taken together, our results demonstrated that LIMK1 functions as a metastasis promoter in gastric cancer by inhibiting LIMK1-p-cofilin and that Dabrafenib has the potential to serve as a novel treatment for gastric cancer peritoneal metastasis.

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Most cited references 23

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Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Marco Gerlinger, Andrew J. Rowan, Stuart Horswell … (2012)

Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).

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Genome-scale CRISPR-Cas9 knockout screening in human cells.

Ophir Shalem, Neville Sanjana, Ella Hartenian … (2014)

The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.

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Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase.

M. Maekawa, T Ishizaki, S Boku … (1999)

The actin cytoskeleton undergoes extensive remodeling during cell morphogenesis and motility. The small guanosine triphosphatase Rho regulates such remodeling, but the underlying mechanisms of this regulation remain unclear. Cofilin exhibits actin-depolymerizing activity that is inhibited as a result of its phosphorylation by LIM-kinase. Cofilin was phosphorylated in N1E-115 neuroblastoma cells during lysophosphatidic acid-induced, Rho-mediated neurite retraction. This phosphorylation was sensitive to Y-27632, a specific inhibitor of the Rho-associated kinase ROCK. ROCK, which is a downstream effector of Rho, did not phosphorylate cofilin directly but phosphorylated LIM-kinase, which in turn was activated to phosphorylate cofilin. Overexpression of LIM-kinase in HeLa cells induced the formation of actin stress fibers in a Y-27632-sensitive manner. These results indicate that phosphorylation of LIM-kinase by ROCK and consequently increased phosphorylation of cofilin by LIM-kinase contribute to Rho-induced reorganization of the actin cytoskeleton.

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Author and article information

Contributors

Guiying Wang:

ORCID: http://orcid.org/0000-0002-8743-325X

wangguiyingtgzy@163.com

Jun Yu:

ORCID: http://orcid.org/0000-0001-5008-2153

junyu@cuhk.edu.hk

Enders Kwok Wai Ng:

ORCID: http://orcid.org/0000-0001-7219-5810

endersng@surgery.cuhk.edu.hk

Journal

Journal ID (nlm-ta): Oncogene

Journal ID (iso-abbrev): Oncogene

Title: Oncogene

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0950-9232

ISSN (Electronic): 1476-5594

Publication date (Electronic): 21 April 2021

Publication date PMC-release: 21 April 2021

Publication date (Print): 2021

Volume: 40

Issue: 19

Pages: 3422-3433

Affiliations

[1 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, , The Chinese University of Hong Kong, ; Hong Kong, China

[2 ]GRID grid.256883.2, ISNI 0000 0004 1760 8442, Department of Surgery, , Hebei Medical University 4th Hospital, ; Shijiazhuang, China

[3 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Surgery, , The Chinese University of Hong Kong, ; Hong Kong, China

[4 ]GRID grid.411918.4, ISNI 0000 0004 1798 6427, Department of Gastroenterology, , Tianjin Medical University Cancer Hospital, City Key Laboratory of Tianjin Cancer Center and National Clinical Research Center for Cancer, ; Tianjin, China

[5 ]GRID grid.256883.2, ISNI 0000 0004 1760 8442, Department of Endocrinology, , Hebei Medical University 2nd Hospital, ; Shijiazhuang, China

[6 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Anatomical and Cellular Pathology, , The Chinese University of Hong Kong, ; Hong Kong, China

Author information

Chi Chun Wong http://orcid.org/0000-0003-1362-3541

Wei Kang http://orcid.org/0000-0002-4651-677X

Ka Fai To http://orcid.org/0000-0003-4919-3707

Philip Wai Yan Chiu http://orcid.org/0000-0001-9292-112X

Guiying Wang http://orcid.org/0000-0002-8743-325X

Jun Yu http://orcid.org/0000-0001-5008-2153

Enders Kwok Wai Ng http://orcid.org/0000-0001-7219-5810

Article

Publisher ID: 1656

DOI: 10.1038/s41388-021-01656-1

PMC ID: 8116207

PubMed ID: 33883692

SO-VID: 3eb3cd68-b9c2-4b28-b2f6-0504cd97aec9

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 12 September 2020

Date revision received : 6 December 2020

Date accepted : 13 January 2021

Funding

Funded by: FundRef https://doi.org/10.13039/501100002855, Ministry of Science and Technology of the People’s Republic of China (Chinese Ministry of Science and Technology);

Award ID: MOST-2016YFC1303200

Award Recipient : Jun Yu

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81972576

Award Recipient : Jun Yu

Funded by: RGC-CRF Hong Kong (C7065-18G); Vice-Chancellor’s Discretionary Fund CUHK; Shenzhen Virtual University Park Support Scheme to CUHK Shenzhen Research Institute.

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: metastasis,molecular biology

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: metastasis, molecular biology

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LIMK1 promotes peritoneal metastasis of gastric cancer and is a therapeutic target

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Karger: Oncology

Most cited references 23

Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Genome-scale CRISPR-Cas9 knockout screening in human cells.

Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase.

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