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Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways

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Abstract

Background

Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets.

Methods

Killer cell lectin-like receptor G2 (KLRG2) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small interfering RNA-mediated KLRG2 knockdown in human GC cell lines was used to investigate KLRG2 involvement in signaling pathways and functional behaviors in vitro and in vivo. Clinicopathological data were analyzed in patients stratified according to tumor KLRG2 mRNA expression.

Results

KLRG2 knockdown in GC cells decreased cell proliferation, migration, and invasion; caused cell cycle arrest in G2/M phase; induced apoptosis via caspase activation; suppressed JAK/STAT and MAPK-ERK1/2 pathway activities; and upregulated p53 and p38 MAPK activities. In mouse xenograft models of peritoneal metastasis, the number and weight of disseminated GC nodules were decreased by KLRG2 knockdown. High tumor levels of KLRG2 mRNA were significantly associated with lower 5-year overall survival (OS) and relapse-free survival (RFS) rates in patients with Stage I–III GC (5-year OS rate: 64.4% vs. 80.0%, P = 0.009; 5-year RFS rate: 62.8% vs. 78.1%, P = 0.030).

Conclusions

KLRG2 knockdown attenuated the malignant phenotypes of GC cells via downregulation of JAK/STAT and MAPK-ERK1/2 pathway activity and upregulation of p38 MAPK and p53. Targeted suppression of KLRG2 may serve as a new treatment approach for GC.

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Acknowledgements

We thank Anne M. O’Rourke, PhD, from Edanz (www.edanz.com/ac) for editing a draft of this manuscript.

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No funding was received.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan

    Yuki Ito, Mitsuro Kanda, Masahiro Sasahara, Chie Tanaka, Dai Shimizu, Shinichi Umeda, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Goro Nakayama & Yasuhiro Kodera

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  1. Yuki Ito
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  2. Mitsuro Kanda
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Correspondence to Mitsuro Kanda.

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Conflict of interest

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Ethics approval and consent to participate

This study conformed to the ethical guidelines of the World Medical Association Declaration of Helsinki (2013) Ethical Principles for Medical Research Involving Human Subjects and was approved by the Institutional Review Board of Nagoya University (approval no. 2014-0043). Written informed consent was obtained from all patients for the use of clinical samples and data. The Animal Research Committee of Nagoya University approved the experiments using animals (approval no. 28210).

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Supplementary Information

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10120_2024_1480_MOESM1_ESM.jpg

Supplementary file1 Supplementary Fig. 1. Knockdown efficiency of KLRG2 siRNA by RT-qPCR on Day 0, Day 2, Day 4, and Day 6 (JPG 3515 KB)

10120_2024_1480_MOESM2_ESM.jpg

Supplementary file2 Supplementary Fig. 2. Expression level of proteins involved in intracellular signaling pathways evaluated by Simple Western assays. a JAK/STAT pathway. b p53. c Cyclins. d p38 MAPK pathway. e ERK1/2 pathway (JPG 5015 KB)

10120_2024_1480_MOESM3_ESM.jpg

Supplementary file3 Supplementary Fig. 3. Immunofluorescence microscopy of MKN1 labeled with KLRG2-Ab (green), Actin (red), and DAPI (blue) (JPG 2684 KB)

Supplementary file4 (DOCX 27 KB)

Supplementary file5 (DOCX 35 KB)

Supplementary file6 (DOCX 35 KB)

Supplementary file7 (DOCX 33 KB)

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Ito, Y., Kanda, M., Sasahara, M. et al. Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways. Gastric Cancer 27, 506–518 (2024). https://doi.org/10.1007/s10120-024-01480-y

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