Forkhead box protein K1‑regulated neurexophilin 4 promotes proliferation, metastasis and glycolysis in colorectal cancer

Fan,Qiulin; He,Wan; Shang,Yuanjiang

doi:10.3892/etm.2023.12133

Forkhead box protein K1‑regulated neurexophilin 4 promotes proliferation, metastasis and glycolysis in colorectal cancer

Authors:
- Qiulin Fan
- Wan He
- Yuanjiang Shang
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Affiliations: Center for Reproductive Medicine, Shanghai Tenth People's Hospital, Shanghai 200072, P.R. China, Department of Blood Transfusion, Shanghai Tenth People's Hospital, Shanghai 200072, P.R. China, Clinical Laboratory, Shanghai Tenth People's Hospital, Shanghai 200072, P.R. China
Published online on: July 25, 2023 https://doi.org/10.3892/etm.2023.12133
Article Number: 434
Copyright: © Fan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) is a common malignant tumor. At present, the in‑depth study of the formation, development and treatment of CRC at the molecular and gene levels is a research hot spot. Neurexophilin 4 (NXPH4) expression has been revealed to be abnormally elevated in several types of cancer, but its expression in CRC has not yet been reported. First, relevant databases were used to predict the expression of NXPH4 in CRC and its association with the survival rate of patients with CRC. Subsequently, the expression of NXPH4 in CRC cells was verified through cell experiments. Cell Counting Kit‑8, 5‑ethynyl‑2'‑deoxyuridine staining, flow cytometry, wound healing assay, Transwell assay, western blotting and the kits were used to detect the effects of NXPH4 knockdown in CRC cells on cell proliferation, invasion, migration and glycolysis. The association between NXPH4 and forkhead box protein K1 (FOXK1) was predicted using the JASPAR database, and verified through luciferase reporter gene and chromatin immunoprecipitation experiments. The NXPH4 regulation mechanism was also discussed. NXPH4 was revealed to be highly expressed in CRC. NXPH4 knockdown in CRC cells could significantly inhibit cell proliferation and induce apoptosis. NXPH4 knockdown inhibited cell invasion, migration and glycolysis. The aforementioned process could be reversed by further FOXK1 overexpression in CRC cells. In conclusion, FOXK1‑regulated NXPH4 promotes proliferation, metastasis and glycolysis in CRC.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018.PubMed/NCBI View Article : Google Scholar
2	ESMO Guidelines Working Group; Van Cutsem EJD. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 18 (Suppl 2):ii25–ii26. 2007.PubMed/NCBI View Article : Google Scholar
3	Kow AWC: Hepatic metastasis from colorectal cancer. J Gastrointest Oncol. 10:1274–1298. 2019.PubMed/NCBI View Article : Google Scholar
4	Muller MF, Ibrahim AE and Arends MJ: Molecular pathological classification of colorectal cancer. Virchows Arch. 469:125–134. 2016.PubMed/NCBI View Article : Google Scholar
5	Piawah S and Venook AP: Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer. 125:4139–4147. 2019.PubMed/NCBI View Article : Google Scholar
6	Gui Z, Ying X and Liu C: NXPH4 Used as a new prognostic and immunotherapeutic marker for muscle-invasive bladder cancer. J Oncol. 2022(4271409)2022.PubMed/NCBI View Article : Google Scholar
7	Tang Q, Chen YM, Shen MM, Dai W, Liang H, Liu JN and Gao J: Increased expression of NXPH4 correlates with immune cell infiltration and unfavorable prognosis in hepatocellular carcinoma. J Oncol. 2022(5005747)2022.PubMed/NCBI View Article : Google Scholar
8	Zhou L, Rueda M and Alkhateeb A: Classification of breast cancer Nottingham prognostic index using high-dimensional embedding and residual neural network. Cancers (Basel). 14(934)2022.PubMed/NCBI View Article : Google Scholar
9	Yang Z, Wei B, Qiao A, Yang P, Chen W, Zhen D and Qiu X: A novel EZH2/NXPH4/CDKN2A axis is involved in regulating the proliferation and migration of non-small cell lung cancer cells. Biosci Biotechnol Biochem. 86:340–350. 2022.PubMed/NCBI View Article : Google Scholar
10	Li JH, Liu S, Zhou H, Qu LH and Yang JH: starBase v2.0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 42 (Database issue):D92–D47. 2014.PubMed/NCBI View Article : Google Scholar
11	Lanczky A and Gyorffy B: Web-based survival analysis tool tailored for medical research (KMplot): Development and implementation. J Med Internet Res. 23(e27633)2021.PubMed/NCBI View Article : Google Scholar
12	Fornes O, Castro-Mondragon JA, Khan A, van der Lee R, Zhang X, Richmond PA, Modi BP, Correard S, Gheorghe M, Baranašić D, et al: JASPAR 2020: Update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 48:D87–D92. 2020.PubMed/NCBI View Article : Google Scholar
13	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.PubMed/NCBI View Article : Google Scholar
14	Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut. 66:683–691. 2017.PubMed/NCBI View Article : Google Scholar
15	Stiksma J, Grootendorst DC and van der Linden PW: CA 19-9 as a marker in addition to CEA to monitor colorectal cancer. Clin Colorectal Cancer. 13:239–244. 2014.PubMed/NCBI View Article : Google Scholar
16	Li J, Ma X, Chakravarti D, Shalapour S and DePinho RA: Genetic and biological hallmarks of colorectal cancer. Genes Dev. 35:787–820. 2021.PubMed/NCBI View Article : Google Scholar
17	Lech G, Słotwiński R, Słodkowski M and Krasnodębski IW: Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances. World J Gastroenterol. 22:1745–1755. 2016.PubMed/NCBI View Article : Google Scholar
18	Eun JW, Jang JW, Yang HD, Kim J, Kim SY, Na MJ, Shin E, Ha JW, Jeon S, Ahn YM, et al: Serum proteins, HMMR, NXPH4, PITX1 and THBS4; a panel of biomarkers for early diagnosis of hepatocellular carcinoma. J Clin Med. 11(2128)2022.PubMed/NCBI View Article : Google Scholar
19	Wang D, Zhang P, Liu Z, Xing' Y and Xiao Y: NXPH4 promotes gemcitabine resistance in bladder cancer by enhancing reactive oxygen species and glycolysis activation through modulating NDUFA4L2. Cancers (Basel). 14(3782)2022.PubMed/NCBI View Article : Google Scholar
20	Liu J, Zhang J, Wang Z, Xi Y, Bai L and Zhang Y: Knockdown of circAPLP2 inhibits progression of colorectal cancer by regulating miR-485-5p/FOXK1 axis. Cancer Biother Radiopharm. 36:737–752. 2021.PubMed/NCBI View Article : Google Scholar
21	Han Y, Peng Y, Liu S, Wang X, Cai C, Guo C, Chen Y, Gao L, Huang Q, He M, et al: tRF3008A suppresses the progression and metastasis of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner. J Exp Clin Cancer Res. 41(32)2022.PubMed/NCBI View Article : Google Scholar
22	Wu M, Wang J, Tang W, Zhan X, Li Y, Peng Y, Huang X, Bai Y, Zhao J, Li A, et al: FOXK1 interaction with FHL2 promotes proliferation, invasion and metastasis in colorectal cancer. Oncogenesis. 5(e271)2016.PubMed/NCBI View Article : Google Scholar