Evidence map›Paper›PMID 39400978›Full record

ArticleCancer medicine2024

miR-4448/Girdin/Akt/AMPK axis inhibits EZH2-mediated EMT and tumorigenesis in small-cell lung cancer.

Nobuyuki Koyama, Yuichi Ishikawa, Hiromitsu Ohta, Takuya Aoki, Hiroyuki Kyoyama, Kazutetsu Aoshiba, Kazutsugu Uematsu

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Article in Cancer medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

7 authors.

Nobuyuki KoyamaDepartment of Respiratory Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan.ORCID https://orcid.org/0000-0002-3989-2275
Yuichi IshikawaDepartment of Pathology, School of Medicine, International University of Health and Welfare, Minato-ku, Tokyo, Japan.ORCID https://orcid.org/0000-0002-9594-5845
Hiromitsu OhtaClinical Department of Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama-shi, Saitama, Japan.
Takuya AokiDepartment of Clinical Oncology, Hachioji Medical Center, Tokyo Medical University, Hachioji-shi, Tokyo, Japan.
Hiroyuki KyoyamaDepartment of Respiratory Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan.
Kazutetsu AoshibaDepartment of Pulmonary Medicine, Ibaraki Medical Center, Tokyo Medical University, Inashiki-gun, Ibaraki, Japan.
Kazutsugu UematsuDepartment of Respiratory Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan.

Funding

Japan Society for the Promotion of Science 26461195Smoking Research Foundation 2019T013
6 · The paper itself

Abstract

backgroundSmall-cell lung cancer (SCLC) shows high enhancer of zeste homolog 2 (EZH2) expressions. EZH2-mediated epigenetics promote epithelial-mesenchymal transition (EMT), enhancing invasive and metastatic potential in malignancies. MicroRNAs (miRNAs), small noncoding RNAs, modulate EMT, determining tumor phenotypes. However, the association between miRNAs and EZH2 in SCLC remains to be clarified-we aimed to identify a novel tumorigenic mechanism through miRNAs, EZH2, and EMT in SCLC, leading to future therapeutic applications.

methodsWe analyzed EZH2 and E-cadherin expressions in lung cancer cell lines and tumor tissues from 34 SCLC patients and confirmed EZH2 siRNA-mediated EMT inhibition. miRNA expression profiles were compared between EZH2 knockdown SCLC cells and negative control SCLC cells using miRNA array. We identified a target miRNA of EZH2 showing expressional differences in EZH2-knockdown cells and analyzed the impact of the miRNA on EZH2-mediated EMT and tumorigenesis.

resultsAll SCLC cells showed increased EZH2 and decreased E-cadherin expressions. SCLC tissues had higher EZH2 and lower E-cadherin expressions than other lung cancer tissues. miRNA array revealed that miR-4448 expression increased in EZH2-knockdown SCLC cells. miR-4448 overexpression reduced tumor cell growth and prevented EMT. miR-4448 bound to the 3'UTR of the girdin gene and suppressed its expression, thereby decreasing Akt phosphorylation at Ser473. Attenuated Akt phosphorylation resulted in AMP-activated protein kinase (AMPK) phosphorylation at Thr172 and 183, enhancing EZH2 phosphorylation at Thr311.

conclusionSCLC characterized high EZH2 expression and promoted EMT, compared with non-small cell lung cancer. miR-4448 inhibited Girdin expression, reducing Akt phosphorylation, and enhancing AMPK and EZH2 phosphorylation. Eventually, miR-4448 prevented EZH2-mediated EMT and tumorigenesis by modulating the Girdin/Akt/AMPK axis in SCLC. miR-4448 might be a potential SCLC inhibitor.

Indexed as

Enhancer of Zeste Homolog 2 ProteinEpithelial-Mesenchymal TransitionGene Expression Regulation, NeoplasticLung NeoplasmsMicroRNAsProto-Oncogene Proteins c-aktSmall Cell Lung CarcinomaAMP-Activated Protein KinasesAnimalsCadherinsCarcinogenesisCell Line, TumorCell MovementCell ProliferationFemaleHumansAMP-Activated Protein KinasesCadherinsEnhancer of Zeste Homolog 2 ProteinEZH2 protein, humanMicrofilament ProteinsMicroRNAsProto-Oncogene Proteins c-aktAktAMP‐activated protein kinaseenhancer of zeste homolog 2epithelial‐mesenchymal transitionGirdinmiR‐4448

Identifiers

PMID39400978
PMCPMC11476246

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.