Role of NPC2 protein in promoting gastric cancer progression through the MEK/ERK and JNK signaling pathways

doi:10.3877/cma.j.issn.2095-2015.2026.05.007

Abstract

Abstract:

Objective

To investigate the role of NPC2 (Niemann-Pick C2) protein in gastric cancer cells and its regulatory mechanisms through the MEK/ERK and JNK signaling pathways.

Methods

The expression levels of NPC2 in normal human cells and gastric carcinoma cell lines were detected. The cell proliferation, cloning, migration and invasion abilities were evaluated, and the phosphorylation levels of the pathways were detected.

Results

NPC2 expression in gastric cancer cells was significantly higher than that in normal epithelial cells, with the highest expression observed in AGS cells (P<0.01). Knockdown of NPC2 significantly inhibited cell proliferation, colony formation, migration, and invasion abilities (P<0.05). NPC2 knockdown also resulted in a significant decrease in the phosphorylation levels of the MEK/ERK and JNK pathways (P<0.05). Overexpression of NPC2 promoted AGS cell proliferation, colony formation, migration, and invasion (P<0.05), while the MEK/ERK and JNK pathway inhibitor E6201 inhibited these biological processes.

Conclusion

NPC2 promotes the progression of gastric cancer by activating the MEK/ERK and JNK signaling pathways, and may represent a potential therapeutic target.

Key words: Gastric cancer, NPC2 protein, Cell proliferation, Migration and invasion

Yunzhuang Yao, Yan Tian, Jing Sun, Juan Wang, Zibai Wei. Role of NPC2 protein in promoting gastric cancer progression through the MEK/ERK and JNK signaling pathways[J]. Chinese Journal of Digestion and Medical Imageology(Electronic Edition), 2026, 16(05): 430-437.

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URL: https://zhxhbyyxzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-2015.2026.05.007

https://zhxhbyyxzz.cma-cmc.com.cn/EN/Y2026/V16/I05/430

Figures/Tables 6

References 21

[1]	Lee D, Hong JH. Niemann-Pick Disease Type C(NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress[J]. Antioxidants(Basel), 2023, 12(12): 2021.
[2]	龙秀鹏, 陶顺, 阳绅, 等. 槲皮素通过抑制MAPK信号通路改善心力衰竭[J]. 南方医科大学学报, 2025, 45(1): 187-196.
[3]	Ullah R, Yin Q, Snell AH, et al. RAF-MEK-ERK pathway in cancer evolution and treatment[J]. Semin Cancer Biol, 2022, 85: 123-154.
[4]	Wu X, Zhou F, Cheng B, et al. Immune activity score to assess the prognosis, immunotherapy and chemotherapy response in gastric cancer and experimental validation[J]. PeerJ, 2023, 11: e16317.
[5]	Chen K, Zhang X, Sun G, et al. Focusing on the abnormal events of NPC1, NPC2, and NPC1L1 in pan-cancer and further constructing LUAD and KICH prediction models[J]. J Proteome Res, 2024, 23(1): 449-464.
[6]	Xu Y, Wang Y, Zhao W, et al. NPC intracellular cholesterol transporter 2 regulates the anti-apoptotic protein baculoviral inhibitor of apoptosis repeat containing 3 and affects drug resistance in gastric cancer[J]. Cytojournal, 2025, 22: 7.
[7]	Wang ZM, Ning ZL, Ma C, et al. Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma[J]. Heliyon, 2024, 10(6): e27575.
[8]	Huang W, Hu X, He X, et al. TRIM29 facilitates gemcitabine resistance via MEK/ERK pathway and is modulated by circRPS29/ miR-770-5p axis in PDAC[J]. Drug Resist Updat, 2024, 74: 101079.
[9]	Rovida E, Tusa I. Targeting MAPK in Cancer 2.0[J]. Int J Mol Sci, 2022, 23(10): 5702.
[10]	Hendrikse CSE, Theelen PMM, van der Ploeg P, et al. The potential of RAS/RAF/MEK/ERK(MAPK) signaling pathway inhibitors in ovarian cancer: A systematic review and meta-analysis[J]. Gynecol Oncol, 2023, 171: 83-94.
[11]	Najafi S, Barasa L, Huang SY, et al. Discovery of a novel class of benzimidazoles as highly effective agonists of bone morphogenetic protein(BMP) receptor signaling[J]. Sci Rep, 2022, 12(1): 12146.
[12]	Zhang W, Borthakur G, Gao C, et al. The Dual MEK/FLT3 Inhibitor E6201 Exerts Cytotoxic Activity against Acute Myeloid Leukemia Cells Harboring Resistance-Conferring FLT3 Mutations[J]. Cancer Res, 2016, 76(6): 1528-1537.
[13]	Liu W, Liu L, Kuang T, et al. Cholesterol metabolism-related genes predict immune infiltration and prognosis in gastric cancer patients [J]. J Cancer, 2025, 16(7): 2087-2102.
[14]	Pu WF, Yang X, Wang XQ, et al. Stemness signatures reflect prognostic disturbances in gastric cancer[J]. World J Gastrointest Oncol, 2025, 17(7): 107211.
[15]	Najafi S, Barasa L, Huang SY, et al. Discovery of a novel class of benzimidazoles as highly effective agonists of bone morphogenetic protein(BMP) receptor signaling[J]. Sci Rep, 2022, 12(1): 12146.
[16]	Zhang W, Borthakur G, Gao C, et al. The Dual MEK/FLT3 Inhibitor E6201 Exerts Cytotoxic Activity against Acute Myeloid Leukemia Cells Harboring Resistance-Conferring FLT3 Mutations[J]. Cancer Res, 2016, 76(6): 1528-1537.
[17]	Liu W, Liu L, Kuang T, et al. Cholesterol metabolism-related genes predict immune infiltration and prognosis in gastric cancer patients[J]. J Cancer, 2025, 16(7): 2087-2102.
[18]	Pu WF, Yang X, Wang XQ, et al. Stemness signatures reflect prognostic disturbances in gastric cancer[J]. World J Gastrointest Oncol, 2025, 17(7): 107211.
[19]	Li Z, Chen H, Chen Z, et al. Bioinformatics Analysis Reveals Prognostic Significance of the Macrophage Marker Gene Signature in Gastric Adenocarcinoma[J]. Front Biosci(Landmark Ed), 2024, 29(5): 172.
[20]	Liang X, Lu L, Wang N, et al. SBF-1 suppresses colorectal cancer cell growth via modulating cholesterol metabolic reprogramming[J]. Biochem Biophys Res Commun, 2026, 794: 153046.
[21]	Li A, Cui P, Liu L, et al. Multi-omics integration and machine learning identify NPC2 as a prognostic and treatment-responsive regulator in lung adenocarcinoma[J]. Front Immunol, 2026, 16: 1697560.

基因名称	引物序列
NPC2	Forward(F): 5'-TGTGGCTCAGTGGCTTAGG-3'
NPC2	Reverse(R): 5'-CCAGGAAGGGATTTCACACA-3'
MEK	F: 5'-TTGGTGAGCGTGTGGTGTCTG-3'
MEK	R:5'-CAGGTGGGTGTGGGTGTGAAG-3'
ERK	F:5'-GCTCTGTCTCCAGGCTGAAGTG
ERK	R:5'-GCTGAGGAAGAAGAATCGCTTGAAC
JNK	F:5'-CTGGACCAAGCGGACCTAATAGAC
JNK	R:5'-AGTGTGATGTGGTGCTGAGAAGAG
β-actin	F: 5'-ACCCCAAAGCCAACAGA-3'
β-actin	R: 5'-CCAGAGTCCATCACAATACC-3'

基因名称	引物序列
NPC2	Forward(F): 5'-TGTGGCTCAGTGGCTTAGG-3'
NPC2	Reverse(R): 5'-CCAGGAAGGGATTTCACACA-3'
MEK	F: 5'-TTGGTGAGCGTGTGGTGTCTG-3'
MEK	R:5'-CAGGTGGGTGTGGGTGTGAAG-3'
ERK	F:5'-GCTCTGTCTCCAGGCTGAAGTG
ERK	R:5'-GCTGAGGAAGAAGAATCGCTTGAAC
JNK	F:5'-CTGGACCAAGCGGACCTAATAGAC
JNK	R:5'-AGTGTGATGTGGTGCTGAGAAGAG
β-actin	F: 5'-ACCCCAAAGCCAACAGA-3'
β-actin	R: 5'-CCAGAGTCCATCACAATACC-3'

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