MNX1 facilitates the malignant progress of lung adenocarcinoma through transcriptionally upregulating CCDC34

Wu,Junhua; Yue,Chongmei; Xu,Weiguo; Li,Hui; Zhu,Jing; Li,Lin

doi:10.3892/ol.2023.13911

MNX1 facilitates the malignant progress of lung adenocarcinoma through transcriptionally upregulating CCDC34

Authors:
- Junhua Wu
- Chongmei Yue
- Weiguo Xu
- Hui Li
- Jing Zhu
- Lin Li
View Affiliations

Affiliations: Respiratory and Critical Care Medicine, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
Published online on: June 13, 2023 https://doi.org/10.3892/ol.2023.13911
Article Number: 325
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Lung adenocarcinoma (LUAD) represents the most prevalent subtype of lung cancer and typically has high incidence and fatality rates. Motor neuron and pancreas homeobox 1 (MNX1) and coiled‑coil domain‑containing 34 (CCDC34) serve as oncogenes in multiple types of cancer. However, their role in LUAD remains to be elucidated. In the present study, bioinformatics analysis and LUAD cell lines were adopted to examine the expression of MNX1 and CCDC34. The proliferation, migration and invasion abilities of A549 cells were determined using Cell Counting Kit‑8, colony formation, wound‑healing and Transwell assay, and flow cytometry was conducted to assess cell cycle distribution and apoptosis. The interaction between MNX1 and CCDC34 was verified by luciferase reporter and chromatin immunoprecipitation assays. In addition, an in vivo animal model of LUAD was established for validation. The results demonstrated that both MNX1 and CCDC34 were upregulated in LUAD cell lines. MNX1 knockdown significantly suppressed cell proliferation, migration and invasion, hindered cell cycle progression and promoted cell apoptosis in vitro and inhibited tumor growth in vivo. However, the antitumor effect of MNX1 knockdown was weakened by simultaneous CCDC34 overexpression in vitro. In terms of mechanism, MNX1 was demonstrated to directly bind to the CCDC34 promoter and transcriptionally activate CCDC34 expression. In conclusion, the present study highlighted a critical role of the MNX1/CCDC34 axis in regulating LUAD progression, providing novel therapeutic targets for LUAD treatment.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A and Bray F: Cancer statistics for the year 2020: An overview. Int J Cancer. Apr 5–2021.(Epub ahead of print). View Article : Google Scholar
3	Sivakumar S, Lucas FAS, McDowell TL, Lang W, Xu L, Fujimoto J, Zhang J, Futreal PA, Fukuoka J, Yatabe Y, et al: Genomic landscape of atypical adenomatous hyperplasia reveals divergent modes to lung adenocarcinoma. Cancer Res. 77:6119–6130. 2017. View Article : Google Scholar : PubMed/NCBI
4	Xu F, He L, Zhan X, Chen J, Xu H, Huang X, Li Y, Zheng X, Lin L and Chen Y: DNA methylation-based lung adenocarcinoma subtypes can predict prognosis, recurrence, and immunotherapeutic implications. Aging (Albany NY). 12:25275–25293. 2020. View Article : Google Scholar : PubMed/NCBI
5	Chen D, Wang R, Yu C, Cao F, Zhang X, Yan F, Chen L, Zhu H, Yu Z and Feng J: FOX-A1 contributes to acquisition of chemoresistance in human lung adenocarcinoma via transactivation of SOX5. EBioMedicine. 44:150–161. 2019. View Article : Google Scholar : PubMed/NCBI
6	Leotta CG, Federico C, Brundo MV, Tosi S and Saccone S: HLXB9 gene expression, and nuclear location during in vitro neuronal differentiation in the SK-N-BE neuroblastoma cell line. PLoS One. 9:e1054812014. View Article : Google Scholar : PubMed/NCBI
7	Harrison KA, Druey KM, Deguchi Y, Tuscano JM and Kehrl JH: A novel human homeobox gene distantly related to proboscipedia is expressed in lymphoid and pancreatic tissues. J Biol Chem. 269:19968–19975. 1994. View Article : Google Scholar : PubMed/NCBI
8	Woolfe A, Goodson M, Goode DK, Snell P, McEwen GK, Vavouri T, Smith SF, North P, Callaway H, Kelly K, et al: Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol. 3:e72005. View Article : Google Scholar : PubMed/NCBI
9	Habener JF, Kemp DM and Thomas MK: Minireview: Transcriptional regulation in pancreatic development. Endocrinology. 146:1025–1034. 2005. View Article : Google Scholar : PubMed/NCBI
10	Vult von Steyern F, Martinov V, Rabben I, Nja A, de Lapeyriere O and Lomo T: The homeodomain transcription factors Islet 1 and HB9 are expressed in adult alpha and gamma motoneurons identified by selective retrograde tracing. Eur J Neurosci. 11:2093–2102. 1999. View Article : Google Scholar : PubMed/NCBI
11	Bonnefond A, Vaillant E, Philippe J, Skrobek B, Lobbens S, Yengo L, Huyvaert M, Cavé H, Busiah K, Scharfmann R, et al: Transcription factor gene MNX1 is a novel cause of permanent neonatal diabetes in a consanguineous family. Diabetes Metab. 39:276–280. 2013. View Article : Google Scholar : PubMed/NCBI
12	Chen H, Zeng L, Zheng W, Li X and Lin B: Increased expression of microRNA-141-3p improves necrotizing enterocolitis of neonates through targeting MNX1. Front Pediatr. 8:3852020. View Article : Google Scholar : PubMed/NCBI
13	Merello E, De Marco P, Ravegnani M, Riccipetitoni G, Cama A and Capra V: Novel MNX1 mutations and clinical analysis of familial and sporadic Currarino cases. Eur J Med Genet. 56:648–654. 2013. View Article : Google Scholar : PubMed/NCBI
14	Das M: MNX1: A novel prostate cancer oncogene. Lancet Oncol. 17:e5212016. View Article : Google Scholar : PubMed/NCBI
15	Zhu B, Wu Y, Luo J, Zhang Q, Huang J, Li Q, Xu L, Lu E and Ren B: MNX1 promotes malignant progression of cervical cancer via repressing the transcription of p21^cip1. Front Oncol. 10:13072020. View Article : Google Scholar : PubMed/NCBI
16	Yang X, Pan Q, Lu Y, Jiang X, Zhang S and Wu J: MNX1 promotes cell proliferation and activates Wnt/β-catenin signaling in colorectal cancer. Cell Biol Int. 43:402–408. 2019. View Article : Google Scholar : PubMed/NCBI
17	Tian T, Wang M, Zhu Y, Zhu W, Yang T, Li H, Lin S, Dai C, Deng Y, Song D, et al: Expression, clinical significance, and functional prediction of MNX1 in breast cancer. Mol Ther Nucleic Acids. 13:399–406. 2018. View Article : Google Scholar : PubMed/NCBI
18	McFarlane AA, Orriss GL and Stetefeld J: The use of coiled-coil proteins in drug delivery systems. Eur J Pharmacol. 625:101–107. 2009. View Article : Google Scholar : PubMed/NCBI
19	Wang J, Wu X, Dai W, Li J, Xiang L, Tang W, Lin J, Zhang W, Liu G, Yang Q, et al: The CCDC43-ADRM1 axis regulated by YY1, promotes proliferation and metastasis of gastric cancer. Cancer Lett. 482:90–101. 2020. View Article : Google Scholar : PubMed/NCBI
20	Bai L, Yang ZX, Liu JS, Wang DS and Yu HC: Prognostic significance of CCDC137 expression and its association with immune infiltration in hepatocellular carcinoma. Dis Markers. 2022:56386752022. View Article : Google Scholar : PubMed/NCBI
21	Zhang X, Zheng Q, Wang C, Zhou H, Jiang G, Miao Y, Zhang Y, Liu Y, Li Q, Qiu X and Wang E: CCDC106 promotes non-small cell lung cancer cell proliferation. Oncotarget. 8:26662–26670. 2017. View Article : Google Scholar : PubMed/NCBI
22	Kutsche K, Glauner E, Knauf S, Pomarino A, Schmidt M, Schröder B, Nothwang H, Schüler H, Goecke T, Kersten A, et al: Cloning and characterization of the breakpoint regions of a chromosome 11;18 translocation in a patient with hamartoma of the retinal pigment epithelium. Cytogenet Cell Genet. 91:141–147. 2000. View Article : Google Scholar : PubMed/NCBI
23	Lin Z, Qu S, Peng W, Yang P, Zhang R, Zhang P, Guo D, Du J, Wu W, Tao K and Wang J: Up-Regulated CCDC34 contributes to the proliferation and metastasis of hepatocellular carcinoma. Onco Targets Ther. 13:51–60. 2020. View Article : Google Scholar : PubMed/NCBI
24	Geng W, Liang W, Fan Y, Ye Z and Zhang L: Overexpression of CCDC34 in colorectal cancer and its involvement in tumor growth, apoptosis and invasion. Mol Med Rep. 17:465–473. 2018.PubMed/NCBI
25	Gong Y, Qiu W, Ning X, Yang X, Liu L, Wang Z, Lin J, Li X and Guo Y: CCDC34 is up-regulated in bladder cancer and regulates bladder cancer cell proliferation, apoptosis and migration. Oncotarget. 6:25856–25867. 2015. View Article : Google Scholar : PubMed/NCBI
26	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
27	Giglia-Mari G, Zotter A and Vermeulen W: DNA damage response. Cold Spring Harb Perspect Biol. 3:a0007452011. View Article : Google Scholar : PubMed/NCBI
28	Shi J, Hua X, Zhu B, Ravichandran S, Wang M, Nguyen C, Brodie SA, Palleschi A, Alloisio M, Pariscenti G, et al: Somatic genomics and clinical features of lung adenocarcinoma: A retrospective study. PLoS Med. 13:e10021622016. View Article : Google Scholar : PubMed/NCBI
29	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
30	Su L, Zhao J, Su H, Wang Y, Huang W, Jiang X and Gao S: CircRNAs in lung adenocarcinoma: Diagnosis and therapy. Curr Gene Ther. 22:15–22. 2022.PubMed/NCBI
31	Chen M, Wu R, Li G, Liu C, Tan L, Xiao K, Ye Y and Qin Z: Motor neuron and pancreas homeobox 1/HLXB9 promotes sustained proliferation in bladder cancer by upregulating CCNE1/2. J Exp Clin Cancer Res. 37:1542018. View Article : Google Scholar : PubMed/NCBI
32	Lambert M, Jambon S, Depauw S and David-Cordonnier MH: Targeting transcription factors for cancer treatment. Molecules. 23:14792018. View Article : Google Scholar : PubMed/NCBI
33	Harrison KA, Thaler J, Pfaff SL, Gu H and Kehrl JH: Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet. 23:71–75. 1999. View Article : Google Scholar : PubMed/NCBI
34	Jiang L, Chen S, Zhao D, Yan J, Chen J, Yang C and Zheng G: MNX1 reduces sensitivity to anoikis by activating TrkB in human glioma cells. Mol Med Rep. 18:3271–3279. 2018.PubMed/NCBI