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Journal of Cancer Research and Clinical Oncology

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Open Access 01-05-2024 | Gastric Cancer | Research

LAMC2 regulates the proliferation, invasion, and metastasis of gastric cancer via PI3K/Akt signaling pathway

Authors: Lulu Cheng, Xiaofei Li, Wenhui Dong, Jing Yang, Pengmei Li, Xihui Qiang, Jiajun Yin, Lianyi Guo

Published in: Journal of Cancer Research and Clinical Oncology | Issue 5/2024

Abstract

Objectives

Gastric cancer (GC) is a prevalent malignant tumor widely distributed globally, exhibiting elevated incidence and fatality rates. The gene LAMC2 encodes the laminin subunit gamma-2 chain and is found specifically in the basement membrane of epithelial cells. Its expression is aberrant in multiple types of malignant tumors. This research elucidated a link between LAMC2 and the clinical characteristics of GC and investigated the potential involvement of LAMC2 in GC proliferation and advancement.

Materials and methods

LAMC2 expressions were detected in GC cell lines and normal gastric epithelial cell lines via qRT-PCR. Silencing and overexpression of the LAMC2 were conducted by lentiviral transfection. A xenograft mouse model was also developed for in vivo analysis. Cell functional assays were conducted to elucidate the involvement of LAMC2 in cell growth, migration, and penetration. Further, immunoblotting was conducted to investigate the impact of LAMC2 on the activation of signal pathways after lentiviral transfection.

Results

In the findings, LAMC2 expression was markedly upregulated in GC cell lines as opposed to normal gastric epithelial cells. In vitro analysis showed that sh-LAMC2 substantially inhibited GC cell growth, migration, and invasion, while oe-LAMC2 displayed a contrasting effect. Xenograft tumor models demonstrated that oe-LAMC2 accelerated tumor growth via high expression of Ki-67. Immunoblotting analysis revealed a substantial decrease in various signaling pathway proteins, PI3K, p-Akt, and Vimentin levels upon LAMC2 knockdown, followed by increased E-cadherin expression. Conversely, its overexpression exhibited contrasting effects. Besides, epithelial-mesenchymal transition (EMT) was accelerated by LAMC2.

Conclusion

This study provides evidence indicating that LAMC2, by stimulating signaling pathways, facilitated EMT and stimulated the progression of GC cells in laboratory settings and mouse models. Research also explored that the abnormal LAMC2 expression acts as a biomarker for GC.

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Akinleye A, Avvaru P, Furqan M, Song Y, Liu D (2013) Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J Hematol Oncol 6(1):88. https://doi.org/10.1186/1756-8722-6-88CrossRefPubMedPubMedCentral

Babaei G, Aziz SG, Jaghi N (2021) EMT, cancer stem cells and autophagy. The three main axes of metastasis. Biomed Pharmacother 133:110909. https://doi.org/10.1016/j.biopha.2020.110909CrossRefPubMed

Bamodu OA, Chang HL, Ong JR, Lee WH, Yeh CT, Tsai JT (2020) Elevated PDK1 expression drives PI3K/AKT/MTOR signaling promotes radiation-resistant and dedifferentiated phenotype of hepatocellular carcinoma. Cells. https://doi.org/10.3390/cells9030746CrossRefPubMedPubMedCentral

Cen W, Li J, Tong C, Zhang W, Zhao Y, Lu B, Yu J (2021) Intrahepatic cholangiocarcinoma cells promote epithelial-mesenchymal transition of hepatocellular carcinoma cells by secreting LAMC2. J Cancer 12(12):3448–3457. https://doi.org/10.7150/jca.55627CrossRefPubMedPubMedCentral

Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564. https://doi.org/10.1126/science.1203543CrossRefPubMed

Chai C, Song LJ, Han SY, Li XQ, Li M (2018) MicroRNA-21 promotes glioma cell proliferation and inhibits senescence and apoptosis by targeting SPRY1 via the PTEN/PI3K/AKT signaling pathway. CNS Neurosci Ther 24(5):369–380. https://doi.org/10.1111/cns.12785CrossRefPubMedPubMedCentral

Chandrashekar DS, Bashel B, Balasubramanya S, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, Varambally S (2017) UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19(8):649–658. https://doi.org/10.1016/j.neo.2017.05.002CrossRefPubMedPubMedCentral

Chung AE, Jaffe R, Freeman IL, Vergnes JP, Braginski JE, Carlin B (1979) Properties of a basement membrane-related glycoprotein synthesized in culture by a mouse embryonal carcinoma-derived cell line. Cell 16(2):277–287. https://doi.org/10.1016/0092-8674(79)90005-9CrossRefPubMed

Domogatskaya A, Rodin S, Tryggvason K (2012) Functional diversity of laminins. Annu Rev Cell Dev Biol 28:523–553. https://doi.org/10.1146/annurev-cellbio-101011-155750CrossRefPubMed

Erice O, Narayanan S, Feliu I (2023) LAMC2 regulates key transcriptional and targetable effectors to support pancreatic cancer growth. Clin Cancer Res 29(6):1137–1154. https://doi.org/10.1158/1078-0432.CCR-22-0794CrossRefPubMed

Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, Znaor A, Bray F (2019) Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 144(8):1941–1953. https://doi.org/10.1002/ijc.31937CrossRefPubMed

Ferreira RM et al (2022) Activation of laminin gamma2 by helicobacter pylori promotes invasion and survival of gastric cancer cells with e-cadherin defects. J Infect Dis 226(12):2226–2237. https://doi.org/10.1093/infdis/jiac397CrossRefPubMed

Fitzmaurice C, Abate D, Abbasi N, Abbastabar H (2019) Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. JAMA Oncol 5(12):1749–1768. https://doi.org/10.1001/jamaoncol.2019.2996CrossRefPubMedPubMedCentral

Fu T, Liu JX, Xie J, Gao Z, Yang Z (2022) LAMC2 as a prognostic biomarker in human cancer: a systematic review and meta-analysis. BMJ Open 12(11):e63682. https://doi.org/10.1136/bmjopen-2022-063682CrossRef

Gotte M, Kovalszky I (2018) Extracellular matrix functions in lung cancer. Matrix Biol 73:105–121. https://doi.org/10.1016/j.matbio.2018.02.018CrossRefPubMed

Hsu HS et al (2020) Involvement of collagen XVII in pluripotency gene expression and metabolic reprogramming of lung cancer stem cells. J Biomed Sci 27(1):5. https://doi.org/10.1186/s12929-019-0593-yCrossRefPubMedPubMedCentral

Huang C, Chen J (2021) Laminin332 mediates proliferation, apoptosis, invasion, migration and epithelialtomesenchymal transition in pancreatic ductal adenocarcinoma. Mol Med Rep. https://doi.org/10.3892/mmr.2020.11649CrossRefPubMedPubMedCentral

Huang D, Du C, Ji D, Xi J, Gu J (2017) Overexpression of LAMC2 predicts poor prognosis in colorectal cancer patients and promotes cancer cell proliferation, migration, and invasion. Tumour Biol 39(6):1393383815. https://doi.org/10.1177/1010428317705849CrossRef

Huang Y, Hong W, Wei X (2022) The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol 15(1):129. https://doi.org/10.1186/s13045-022-01347-8CrossRefPubMedPubMedCentral

Ji X et al (2024) Mitochondrial ribosomal protein L12 potentiates hepatocellular carcinoma by regulating mitochondrial biogenesis and metabolic reprogramming. Metabolism 152:155761. https://doi.org/10.1016/j.metabol.2023.155761CrossRefPubMed

Jin Y et al (2022) Activation of PI3K/AKT pathway is a potential mechanism of treatment resistance in small cell lung cancer. Clin Cancer Res 28(3):526–539. https://doi.org/10.1158/1078-0432.CCR-21-1943CrossRefPubMed

Jin Z, Sato Y, Kawashima M, Kanehisa M (2023) KEGG tools for classification and analysis of viral proteins. Protein Sci 32(12):e4820. https://doi.org/10.1002/pro.4820CrossRefPubMedPubMedCentral

Joshi SS, Badgwell BD (2021) Current treatment and recent progress in gastric cancer. CA Cancer J Clin 71(3):264–279. https://doi.org/10.3322/caac.21657CrossRefPubMedPubMedCentral

Lei ZN et al (2022) Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 7(1):358. https://doi.org/10.1038/s41392-022-01190-wCrossRefPubMedPubMedCentral

Li D et al (2023) CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. Oncogene 42(2):83–98. https://doi.org/10.1038/s41388-022-02537-xCrossRefPubMed

Li Y et al (2024) Autophagy activation is required for N6-methyladenosine modification to regulate ferroptosis in hepatocellular carcinoma. Redox Biol 69:102971. https://doi.org/10.1016/j.redox.2023.102971CrossRefPubMed

Liang Y, Chen X, Wu Y, Li J, Zhang S, Wang K, Guan X, Yang K, Bai Y (2018) LncRNA CASC9 promotes esophageal squamous cell carcinoma metastasis through upregulating LAMC2 expression by interacting with the CREB-binding protein. Cell Death Differ 25(11):1980–1995. https://doi.org/10.1038/s41418-018-0084-9CrossRefPubMedPubMedCentral

Liu W, Gou H, Wang X, Li X, Hu X, Su H, Li S, Yu J (2021) TTPAL promotes gastric tumorigenesis by directly targeting NNMT to activate PI3K/AKT signaling. Oncogene 40(49):6666–6679. https://doi.org/10.1038/s41388-021-01838-xCrossRefPubMedPubMedCentral

Liu H et al (2022) lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus. Cell Death Differ 29(3):627–641. https://doi.org/10.1038/s41418-021-00879-9CrossRefPubMed

Lv Y et al (2021) LncRNA PINK1-AS promotes Galphai1-driven gastric cancer tumorigenesis by sponging microRNA-200a. Oncogene 40(22):3826–3844. https://doi.org/10.1038/s41388-021-01812-7CrossRefPubMed

Moon YW et al (2015) LAMC2 enhances the metastatic potential of lung adenocarcinoma. Cell Death Differ 22(8):1341–1352. https://doi.org/10.1038/cdd.2014.228CrossRefPubMedPubMedCentral

Pastushenko I, Blanpain C (2019) EMT transition states during tumor progression and metastasis. Trends Cell Biol 29(3):212–226. https://doi.org/10.1016/j.tcb.2018.12.001CrossRefPubMed

Qu X et al (2023) Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer. Drug Resist Updat 68:100936. https://doi.org/10.1016/j.drup.2023.100936CrossRefPubMed

Rahman R, Asombang AW, Ibdah JA (2014) Characteristics of gastric cancer in Asia. World J Gastroenterol 20(16):4483–4490. https://doi.org/10.3748/wjg.v20.i16.4483CrossRefPubMedPubMedCentral

Rousselle P, Scoazec JY (2020) Laminin 332 in cancer: when the extracellular matrix turns signals from cell anchorage to cell movement. Semin Cancer Biol 62:149–165. https://doi.org/10.1016/j.semcancer.2019.09.026CrossRefPubMed

Sentani K et al (2014) Clinicopathological significance of MMP-7, laminin γ2 and EGFR expression at the invasive front of gastric carcinoma. Gastric Cancer 17(3):412–422. https://doi.org/10.1007/s10120-013-0302-6CrossRefPubMed

Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics. CA Cancer J Clin 72(1):7–33. https://doi.org/10.3322/caac.21708CrossRefPubMed

Stanciu S et al (2022) Targeting PI3K/AKT/mTOR signaling pathway in pancreatic cancer: from molecular to clinical aspects. Int J Mol Sci. https://doi.org/10.3390/ijms231710132CrossRefPubMedPubMedCentral

Szklarczyk D et al (2023) The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucl Acids Res 51(D1):D638–D646. https://doi.org/10.1093/nar/gkac1000CrossRefPubMed

Timpl R, Rohde H, Robey PG, Rennard SI, Foidart JM, Martin GR (1979) Laminin–a glycoprotein from basement membranes. J Biol Chem 254(19):9933–9937CrossRefPubMed

Verma S, Ishteyaque S, Washimkar KR, Verma S, Nilakanth MM (2024) Mitochondrial-mediated nuclear remodeling and macrophage polarizations: a key switch from liver fibrosis to HCC progression. Exp Cell Res 434(1):113878. https://doi.org/10.1016/j.yexcr.2023.113878CrossRefPubMed

Xu L et al (2017) Nuclear Drosha enhances cell invasion via an EGFR-ERK1/2-MMP7 signaling pathway induced by dysregulated miRNA-622/197 and their targets LAMC2 and CD82 in gastric cancer. Cell Death Dis 8(3):e2642. https://doi.org/10.1038/cddis.2017.5CrossRefPubMedPubMedCentral

Xu H, Wang J, Al-Nusaif M, Ma H, Le W (2024) CCL2 promotes metastasis and epithelial-mesenchymal transition of non-small cell lung cancer via PI3K/Akt/mTOR and autophagy pathways. Cell Prolif 57(3):e13560. https://doi.org/10.1111/cpr.13560CrossRefPubMed

Yu L et al (2022) Complete loss of miR-200 family induces EMT associated cellular senescence in gastric cancer. Oncogene 41(1):26–36. https://doi.org/10.1038/s41388-021-02067-yCrossRefPubMed

Zhang Z et al (2023) The PI3K-AKT-mTOR signaling pathway mediates the cytoskeletal remodeling and epithelial-mesenchymal transition in bladder outlet obstruction. Heliyon 9(11):e21281. https://doi.org/10.1016/j.heliyon.2023.e21281CrossRefPubMedPubMedCentral

Zhou B et al (2022) Correction: Interaction between laminin-5gamma2 and integrin beta1 promotes the tumor budding of colorectal cancer via the activation of Yes-associated proteins. Oncogene 41(38):4405–4406. https://doi.org/10.1038/s41388-022-02422-7CrossRefPubMed

Zhu Y, Liu X, Zhao P, Zhao H, Gao W, Wang L (2020) Celastrol suppresses glioma vasculogenic mimicry formation and angiogenesis by blocking the PI3K/Akt/mTOR signaling pathway. Front Pharmacol 11:25. https://doi.org/10.3389/fphar.2020.00025CrossRefPubMedPubMedCentral

Title: LAMC2 regulates the proliferation, invasion, and metastasis of gastric cancer via PI3K/Akt signaling pathway
Authors: Lulu Cheng
Xiaofei Li
Wenhui Dong
Jing Yang
Pengmei Li
Xihui Qiang
Jiajun Yin
Lianyi Guo
Publication date: 01-05-2024
Publisher: Springer Berlin Heidelberg
Keywords: Gastric Cancer
Gastric Cancer
Published in: Journal of Cancer Research and Clinical Oncology / Issue 5/2024
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-024-05720-7

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Abstract

Objectives

Materials and methods

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