NPTX1 inhibits pancreatic cancer cell proliferation and migration and enhances chemotherapy sensitivity by targeting RBM10

Wu,Jing; Liu,Gaifang; An,Kang; Shi,Linping

doi:10.3892/ol.2022.13275

NPTX1 inhibits pancreatic cancer cell proliferation and migration and enhances chemotherapy sensitivity by targeting RBM10

Authors:
- Jing Wu
- Gaifang Liu
- Kang An
- Linping Shi
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Affiliations: Department of Digestion, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
Published online on: March 16, 2022 https://doi.org/10.3892/ol.2022.13275
Article Number: 154
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pancreatic cancer (PC), one of the deadliest diseases worldwide, has exhibited an increasing incidence rate in recent years. The present study aimed to explore the biological mechanism of PC. Therefore, the expression levels of neuronal pentraxin 1 (NPTX1) and RNA‑binding protein 10 (RBM10) were detected in PC cell lines using reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analyses prior to or following NPTX1 and RBM10 overexpression. Additionally, the proliferative ability of PANC‑1 and BxPC‑3 cells treated with or without gemcitabine (GEM) and cisplatin (DDP) was evaluated using Cell Counting Kit‑8 assay. Cell apoptosis and the expression levels of apoptosis‑related proteins were determined by TUNEL assay and western blot analysis, respectively. Furthermore, wound healing and Transwell assays were performed to measure the migration and invasion abilities of PANC‑1 and BxPC‑3 cells. The interaction between RBM10 and NPTX1 mRNA was detected by RNA binding protein immunoprecipitation (RIP) assay. Additionally, cells were treated with actinomycin D to verify the regulatory effect of RBM10 on NPTX1 expression. This effect was further confirmed by RT‑qPCR analysis. The results showed that NPTX1 was downregulated in PC cell lines. In addition, NPTX1 overexpression inhibited the proliferation and promoted apoptosis in PC cells. The results from the wound healing and Transwell assays revealed that the migration and invasion abilities of PANC‑1 and BxPC‑3 cells were reduced following NPTX1 overexpression. However, treatment of NPTX1‑overexpressing cells with GEM or DDP attenuated PC cell viability. In addition, the results of the RIP assay revealed that RBM10 could bind with NPTX1. Furthermore, RBM10 overexpression could regulate NPTX1 expression, as evidenced by actinomycin D experiments. Overall, the results of the present study suggested that NPTX1 could inhibit PC and enhance the sensitivity of PC cells to chemotherapy. Additionally, NPTX1 was found to interact with RBM10, indicating that NPTX1 could inhibit PC via targeting RBM10.

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1	Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 57:43–66. 2007. View Article : Google Scholar : PubMed/NCBI
2	Peto R: The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Br J Cancer. 105 (Suppl 2):S12011. View Article : Google Scholar : PubMed/NCBI
3	Wang Y, Yang G, You L, Yang J, Feng M, Qiu J, Zhao F, Liu Y, Cao Z, Zheng L, et al: Role of the microbiome in occurrence, development and treatment of pancreatic cancer. Mol Cancer. 18:1732019. View Article : Google Scholar : PubMed/NCBI
4	Chu LC, Goggins MG and Fishman EK: Diagnosis and detection of pancreatic cancer. Cancer J. 23:333–342. 2017. View Article : Google Scholar : PubMed/NCBI
5	Quaresma M, Coleman MP and Rachet B: 40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971-2011: A population-based study. Lancet. 385:1206–1218. 2015. View Article : Google Scholar : PubMed/NCBI
6	Raimondi S, Maisonneuve P and Lowenfels AB: Epidemiology of pancreatic cancer: An overview. Nat Rev Gastroenterol Hepatol. 6:699–708. 2009. View Article : Google Scholar : PubMed/NCBI
7	Tsui CC, Copeland NG, Gilbert DJ, Jenkins NA, Barnes C and Worley PF: Narp, a novel member of the pentraxin family, promotes neurite outgrowth and is dynamically regulated by neuronal activity. J Neurosci. 16:2463–2478. 1996. View Article : Google Scholar : PubMed/NCBI
8	Schlimgen AK, Helms JA, Vogel H and Perin MS: Neuronal pentraxin, a secreted protein with homology to acute phase proteins of the immune system. Neuron. 14:519–526. 1995. View Article : Google Scholar : PubMed/NCBI
9	Hagihara A, Miyamoto K, Furuta J, Hiraoka N, Wakazono K, Seki S, Fukushima S, Tsao MS, Sugimura T and Ushijima T: Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers. Oncogene. 23:8705–8710. 2004. View Article : Google Scholar : PubMed/NCBI
10	Peng X, Pan K, Zhao W, Zhang J, Yuan S, Wen X, Zhou W and Yu Z: NPTX1 inhibits colon cancer cell proliferation through down-regulating cyclin A2 and CDK2 expression. Cell Biol Int. 42:589–597. 2018. View Article : Google Scholar : PubMed/NCBI
11	Zhou C, Qin Y, Xie Z, Zhang J, Yang M, Li S and Chen R: NPTX1 is a novel epigenetic regulation gene and associated with prognosis in lung cancer. Biochem Biophys Res Commun. 458:381–386. 2015. View Article : Google Scholar : PubMed/NCBI
12	Yue W, Wang T, Zachariah E, Lin Y, Yang CS, Xu Q, DiPaola RS and Tan XL: Transcriptomic analysis of pancreatic cancer cells in response to metformin and aspirin: An implication of synergy. Sci Rep. 5:133902015. View Article : Google Scholar : PubMed/NCBI
13	Yue W, Yang CS, DiPaola RS and Tan XL: Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res (Phila). 7:388–397. 2014. View Article : Google Scholar : PubMed/NCBI
14	Mini E, Nobili S, Caciagli B, Landini I and Mazzei T: Cellular pharmacology of gemcitabine. Ann Oncol. 17 (Suppl 5):v7–v12. 2006. View Article : Google Scholar : PubMed/NCBI
15	Ghosh S: Cisplatin: The first metal based anticancer drug. Bioorg Chem. 88:1029252019. View Article : Google Scholar : PubMed/NCBI
16	Heinemann V: Gemcitabine: Progress in the treatment of pancreatic cancer. Oncology. 60:8–18. 2001. View Article : Google Scholar : PubMed/NCBI
17	Wang X, Ni Q, Jin M, Li Z, Wu Y, Zhao Y and Feng F: Gemcitabine or gemcitabine plus cisplatin for in 42 patients with locally advanced or metastatic pancreatic cancer. Zhonghua Zhong Liu Za Zhi. 24:404–407. 2002.PubMed/NCBI
18	Thiselton DL, McDowall J, Brandau O, Ramser J, d'Esposito F, Bhattacharya SS, Ross MT, Hardcastle AJ and Meindl A: An integrated, functionally annotated gene map of the DXS8026-ELK1 interval on human Xp11.3-Xp11.23: Potential hotspot for neurogenetic disorders. Genomics. 79:560–572. 2002. View Article : Google Scholar : PubMed/NCBI
19	Zhao J, Sun Y, Huang Y, Song F, Huang Z, Bao Y, Zuo J, Saffen D, Shao Z, Liu W and Wang Y: Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing. Sci Rep. 7:404882017. View Article : Google Scholar : PubMed/NCBI
20	Wang K, Bacon ML, Tessier JJ, Rintala-Maki ND, Tang V and Sutherland LC: RBM10 modulates apoptosis and influences TNF-α gene expression. J Cell Death. 5:1–19. 2012. View Article : Google Scholar : PubMed/NCBI
21	Xiao W, Chen X, Li X, Deng K, Liu H, Ma J, Wang Z, Hu Y and Hou J: RBM10 regulates human TERT gene splicing and inhibits pancreatic cancer progression. Am J Cancer Res. 11:157–170. 2021.PubMed/NCBI
22	Zhao Y, Yu Y, Zhao W, You S, Feng M, Xie C, Chi X, Zhang Y and Wang X: As a downstream target of the AKT pathway, NPTX1 inhibits proliferation and promotes apoptosis in hepatocellular carcinoma. Biosci Rep. 39:BSR201816622019. View Article : Google Scholar : PubMed/NCBI
23	Jin X, Di X, Wang R, Ma H, Tian C, Zhao M, Cong S, Liu J, Li R and Wang K: RBM10 inhibits cell proliferation of lung adenocarcinoma via RAP1/AKT/CREB signalling pathway. J Cell Mol Med. 23:3897–3904. 2019. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Method. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
26	Previdi MC, Carotenuto P, Zito D, Pandolfo R and Braconi C: Noncoding RNAs as novel biomarkers in pancreatic cancer: What do we know? Future Oncol. 13:443–453. 2017. View Article : Google Scholar : PubMed/NCBI
27	Gedge K: Pancreatic cancer: A symptomless killer. J Perioper Pract. 27:158–161. 2017.PubMed/NCBI
28	Boles NC, Hirsch SE, Le S, Corneo B, Najm F, Minotti AP, Wang Q, Lotz S, Tesar PJ and Fasano CA: NPTX1 regulates neural lineage specification from human pluripotent stem cells. Cell Rep. 6:724–736. 2014. View Article : Google Scholar : PubMed/NCBI
29	Lu S, Zhou C, Zou B, Zhang H and Feng M: MiR-4295 facilitates cell proliferation and metastasis in head and neck squamous cell carcinoma by targeting NPTX1. Genes Immun. 21:4–12. 2020. View Article : Google Scholar : PubMed/NCBI
30	Miao H, Chen X and Luan Y: Small molecular gemcitabine prodrugs for cancer therapy. Curr Med Chem. 27:5562–5582. 2020. View Article : Google Scholar : PubMed/NCBI
31	Shen DW, Pouliot LM, Hall MD and Gottesman MM: Cisplatin resistance: A cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev. 64:706–721. 2012. View Article : Google Scholar : PubMed/NCBI
32	Abrams TJ, Lee LB, Murray LJ, Pryer NK and Cherrington JM: SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2:471–478. 2003.PubMed/NCBI
33	Koch M, Krieger ML, Stölting D, Brenner N, Beier M, Jaehde U, Wiese M, Royer HD and Bendas G: Overcoming chemotherapy resistance of ovarian cancer cells by liposomal cisplatin: Molecular mechanisms unveiled by gene expression profiling. Biochem Pharmacol. 85:1077–1090. 2013. View Article : Google Scholar : PubMed/NCBI
34	Steinberg RL, Thomas LJ, Brooks N, Mott SL, Vitale A, Crump T, Rao MY, Daniels MJ, Wang J, Nagaraju S, et al: Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. J Urol. 203:902–909. 2020. View Article : Google Scholar : PubMed/NCBI
35	Seidman AD: Gemcitabine as single-agent therapy in the management of advanced breast cancer. Oncology (Williston Park). 15 (2 Suppl 3):S11–S14. 2001.
36	Jackson TC, Du L, Janesko-Feldman K, Vagni VA, Dezfulian C, Poloyac SM, Jackson EK, Clark RS and Kochanek PM: The nuclear splicing factor RNA binding motif 5 promotes caspase activation in human neuronal cells, and increases after traumatic brain injury in mice. J Cereb Blood Flow Metab. 35:655–666. 2015. View Article : Google Scholar : PubMed/NCBI
37	Loiselle JJ and Sutherland LC: Differential downregulation of Rbm5 and Rbm10 during skeletal and cardiac differentiation. In Vitro Cell Dev Biol Anim. 50:331–339. 2014. View Article : Google Scholar : PubMed/NCBI
38	Rodor J, FitzPatrick DR, Eyras E and Cáceres JF: The RNA-binding landscape of RBM10 and its role in alternative splicing regulation in models of mouse early development. RNA Biol. 14:45–57. 2017. View Article : Google Scholar : PubMed/NCBI
39	Minaga K, Watanabe T, Hara A, Kamata K, Omoto S, Nakai A, Otsuka Y, Sekai I, Yoshikawa T, Yamao K, et al: Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease. Sci Rep. 10:148792020. View Article : Google Scholar : PubMed/NCBI
40	Fujisawa M, Kanda T, Shibata T, Sasaki R, Masuzaki R, Matsumoto N, Nirei K, Imazu H, Kuroda K, Sugitani M, et al: Involvement of the interferon signaling pathways in pancreatic cancer cells. Anticancer Res. 40:4445–4455. 2020. View Article : Google Scholar : PubMed/NCBI