PCSK9 promotes tumor cell proliferation and migration by facilitating CCL25 secretion in esophageal squamous cell carcinoma

Wang,Haijun; Guo,Qiang; Wang,Mingbo; Liu,Changjiang; Tian,Ziqiang

doi:10.3892/ol.2023.14086

PCSK9 promotes tumor cell proliferation and migration by facilitating CCL25 secretion in esophageal squamous cell carcinoma

Authors:
- Haijun Wang
- Qiang Guo
- Mingbo Wang
- Changjiang Liu
- Ziqiang Tian
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Affiliations: Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050010, P.R. China
Published online on: October 4, 2023 https://doi.org/10.3892/ol.2023.14086
Article Number: 500
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) serves an important role in maintaining plasma cholesterol levels, and fatty acid metabolism is involved in the progression of various types of cancer. In the present study, the role of PCSK9 in the development of esophageal squamous cell carcinoma (ESCC) was investigated. PCSK9 expression was compared between ESCC and normal esophageal epithelial tissues using reverse transcription‑quantitative PCR. In addition, the association between PCSK9 expression and clinical staging and prognosis was assessed by immunohistochemistry. The effects of PCSK9 overexpression or knockdown on cell proliferation was evaluated using Cell Counting Kit‑8 and colony formation assays. The invasion and migration of cancer cells was assessed using wound healing and Transwell assays. Western blotting was performed to evaluate changes in the expression levels of epithelial‑mesenchymal transition (EMT)‑related proteins. ELISA was performed to detect the effects of PCSK9 on chemokine (C‑C motif) ligand 25 (CCL25) secretion. The results revealed that PCSK9 was highly expressed in ESCC tissues compared with that in normal esophageal tissues, and the high expression of PCSK9 was associated with a poor prognosis. Furthermore, PCSK9 could promote the proliferation, migration and invasion of ESCC cells in vitro. Mechanistically, PCSK9 could promote EMT by secreting CCL25. In conclusion, patients with ESCC may benefit from a novel therapeutic strategy based on these findings.

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1	Klingelhöfer D, Zhu Y, Braun M, Brüggmann D, Schöffel N and Groneberg DA: A world map of esophagus cancer research: A critical accounting. J Transl Med. 17:1502019. View Article : Google Scholar : PubMed/NCBI
2	Abnet CC, Arnold M and Wei WQ: Epidemiology of esophageal squamous cell carcinoma. Gastroenterology. 154:360–373. 2018. View Article : Google Scholar : PubMed/NCBI
3	Siegel RL, Miller KD, Fuchs HE and Jemal A: Cancer statistics, 2022. CA Cancer J Clin. 72:7–33. 2022. View Article : Google Scholar : PubMed/NCBI
4	Kelly RJ: Emerging multimodality approaches to treat localized esophageal cancer. J Natl Compr Canc Netw. 17:1009–1014. 2019. View Article : Google Scholar : PubMed/NCBI
5	Gronnier C and Collet D: New trends in esophageal cancer management. Cancers (Basel). 13:30302021. View Article : Google Scholar : PubMed/NCBI
6	Martin-Perez M, Urdiroz-Urricelqui U, Bigas C and Benitah SA: The role of lipids in cancer progression and metastasis. Cell Metab. 34:1675–1699. 2022. View Article : Google Scholar : PubMed/NCBI
7	Lambert G, Sjouke B, Choque B, Kastelein JJP and Hovingh GK: The PCSK9 decade. J Lipid Res. 53:2515–2524. 2012. View Article : Google Scholar : PubMed/NCBI
8	Mahboobnia K, Pirro M, Marini E, Grignani F, Bezsonov EE, Jamialahmadi T and Sahebkar A: PCSK9 and cancer: Rethinking the link. Biomed Pharmacother. 140:1117582021. View Article : Google Scholar : PubMed/NCBI
9	Bonaventura A, Vecchié A, Ruscica M, Grossi F and Dentali F: PCSK9 as a new player in cancer: New opportunity or red herring? Curr Med Chem. 29:960–969. 2022. View Article : Google Scholar : PubMed/NCBI
10	Zhang SZ, Zhu XD, Feng LH, Li XL, Liu XF, Sun HC and Tang ZY: PCSK9 promotes tumor growth by inhibiting tumor cell apoptosis in hepatocellular carcinoma. Exp Hematol Oncol. 10:252021. View Article : Google Scholar : PubMed/NCBI
11	Wang L, Li S, Luo H, Lu Q and Yu S: PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages. J Exp Clin Cancer Res. 41:3032022. View Article : Google Scholar : PubMed/NCBI
12	Xu B, Li S, Fang Y, Zou Y, Song D, Zhang S and Cai Y: Proprotein convertase subtilisin/kexin type 9 promotes gastric cancer metastasis and suppresses apoptosis by facilitating mapk signaling pathway through HSP70 up-regulation. Front Oncol. 10:6096632020. View Article : Google Scholar : PubMed/NCBI
13	Jurisic V: Multiomic analysis of cytokines in immuno-oncology. Expert Rev Proteomics. 17:663–674. 2020. View Article : Google Scholar : PubMed/NCBI
14	Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD and Chodosh LA: The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 8:197–209. 2005. View Article : Google Scholar : PubMed/NCBI
15	Gravdal K, Halvorsen OJ, Haukaas SA and Akslen LA: A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res. 13:7003–7011. 2007. View Article : Google Scholar : PubMed/NCBI
16	Baumgart E, Cohen MS, Silva Neto B, Jacobs MA, Wotkowicz C, Rieger-Christ KM, Biolo A, Zeheb R, Loda M, Libertino JA and Summerhayes IC: Identification and prognostic significance of an epithelial-mesenchymal transition expression profile in human bladder tumors. Clin Cancer Res. 13:1685–1694. 2007. View Article : Google Scholar : PubMed/NCBI
17	Ye X, Tam WL, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E and Weinberg RA: Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 525:256–260. 2015. View Article : Google Scholar : PubMed/NCBI
18	Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, et al: EMT and dissemination precede pancreatic tumor formation. Cell. 148:349–361. 2012. View Article : Google Scholar : PubMed/NCBI
19	Propper DJ and Balkwill FR: Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol. 19:237–253. 2022. View Article : Google Scholar : PubMed/NCBI
20	Johnson-Holiday C, Singh R, Johnson E, Singh S, Stockard CR, Grizzle WE and Lillard JW Jr: CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion. Int J Oncol. 38:1279–1285. 2011.PubMed/NCBI
21	Niu Y, Tang D, Fan L, Gao W and Lin H: CCL25 promotes the migration and invasion of non-small cell lung cancer cells by regulating VEGF and MMPs in a CCR9-dependent manner. Exp Ther Med. 19:3571–3580. 2020.PubMed/NCBI
22	Zhang Z, Sun T, Chen Y, Gong S, Sun X, Zou F and Peng R: CCL25/CCR9 signal promotes migration and invasion in hepatocellular and breast cancer cell lines. DNA Cell Biol. 35:348–357. 2016. View Article : Google Scholar : PubMed/NCBI
23	Zheng Y, Sang M, Liu F, Gu L, Li J, Wu Y and Shan B: Aprepitant inhibits the progression of esophageal squamous cancer by blocking the truncated neurokinin-1 receptor. Oncol Rep. 50:1312023. 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. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Scherbakov AM, Vorontsova SK, Khamidullina AI, Mrdjanovic J, Andreeva OE, Bogdanov FB, Salnikova DI, Jurisic V, Zavarzin IV and Shirinian VZ: Novel pentacyclic derivatives and benzylidenes of the progesterone series cause anti-estrogenic and antiproliferative effects and induce apoptosis in breast cancer cells. Invest New Drugs. 41:142–152. 2023. View Article : Google Scholar : PubMed/NCBI
26	Prasad K and Prabhu GK: Image analysis tools for evaluation of microscopic views of immunohistochemically stained specimen in medical research-a review. J Med Syst. 36:2621–2631. 2012. View Article : Google Scholar : PubMed/NCBI
27	Cheng C, Geng F, Cheng X and Guo D: Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun (Lond). 38:272018.PubMed/NCBI
28	Diao XY and Lin T: Progress in therapeutic strategies based on cancer lipid metabolism. Thorac Cancer. 10:1741–1743. 2019. View Article : Google Scholar : PubMed/NCBI
29	Nickels JT Jr: New links between lipid accumulation and cancer progression. J Biol Chem. 293:6635–6636. 2018. View Article : Google Scholar : PubMed/NCBI
30	Fasolato S, Pigozzo S, Pontisso P, Angeli P, Ruscica M, Savarino E, De Martin S, Lupo MG and Ferri N: PCSK9 levels are raised in chronic HCV patients with hepatocellular carcinoma. J Clin Med. 9:31342020. View Article : Google Scholar : PubMed/NCBI
31	Mbikay M, Sirois F, Gyamera-Acheampong C, Wang GS, Rippstein P, Chen A, Mayne J, Scott FW and Chrétien M: Variable effects of gender and Western diet on lipid and glucose homeostasis in aged PCSK9-deficient C57BL/6 mice CSK9PC57BL/6. J Diabetes. 7:74–84. 2015. View Article : Google Scholar : PubMed/NCBI
32	Ito M, Hiwasa T, Oshima Y, Yajima S, Suzuki T, Nanami T, Sumazaki M, Shiratori F, Funahashi K, Li SY, et al: Association of serum anti-PCSK9 antibody levels with favorable postoperative prognosis in esophageal cancer. Front Oncol. 11:7080392021. View Article : Google Scholar : PubMed/NCBI
33	Lu W and Kang Y: Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev Cell. 49:361–374. 2019. View Article : Google Scholar : PubMed/NCBI
34	Zhang Y, Donaher JL, Das S, Li X, Reinhardt F, Krall JA, Lambert AW, Thiru P, Keys HR, Khan M, et al: Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis. Nat Cell Biol. 24:554–564. 2022. View Article : Google Scholar : PubMed/NCBI
35	Jurisic V, Srdic-Rajic T, Konjevic G, Bogdanovic G and Colic M: TNF-α induced apoptosis is accompanied with rapid CD30 and slower CD45 shedding from K-562 cells. J Membr Biol. 239:115–122. 2011. View Article : Google Scholar : PubMed/NCBI
36	Liu X and Tian X: Long noncoding RNA TCONS_00068220 promotes breast cancer progression by regulating epithelial-mesenchymal transition marker E-cadherin. Med Sci Monit. 27:e9298322021.PubMed/NCBI
37	Sharma PK, Singh R, Novakovic KR, Eaton JW, Grizzle WE and Singh S: CCR9 mediates PI3K/AKT-dependent antiapoptotic signals in prostate cancer cells and inhibition of CCR9-CCL25 interaction enhances the cytotoxic effects of etoposide. Int J Cancer. 127:2020–2030. 2010. View Article : Google Scholar : PubMed/NCBI
38	Stankovic S, Konjevic G, Gopcevic K, Jovic V, Inic M and Jurisic V: Activity of MMP-2 and MMP-9 in sera of breast cancer patients. Pathol Res Pract. 206:241–247. 2010. View Article : Google Scholar : PubMed/NCBI
39	Li J, Muhammad J, Xie T, Sun J, Lei Y, Wei Z, Pan S, Qin H, Shao L, Jiang D and Zhang Q: LINC00853 restrains T cell acute lymphoblastic leukemia invasion and infiltration by regulating CCR9/CCL25. Mol Immunol. 140:267–275. 2021. View Article : Google Scholar : PubMed/NCBI
40	Li J, Zhao C, Wang D, Wang S, Dong H, Wang D, Yang Y, Li J, Cui F, He X and Qin J: ZIM3 activation of CCL25 expression in pulmonary metastatic nodules of osteosarcoma recruits M2 macrophages to promote metastatic growth. Cancer Immunol Immunother. 72:903–916. 2023. View Article : Google Scholar : PubMed/NCBI