PLEK2 mediates metastasis and invasion via α5-nAChR activation in nicotine-induced lung adenocarcinoma
Qiang Li
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorJingtan Li
Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
Search for more papers by this authorJingting Wang
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorJing Wang
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorTong Lu
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Intelligent Technology Innovation Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
Search for more papers by this authorYanfei Jia
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorHaiji Sun
Shandong Intelligent Technology Innovation Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
College of Life Science, Shandong Normal University, Shandong, China
Search for more papers by this authorCorresponding Author
Xiaoli Ma
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
Shandong Intelligent Technology Innovation Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
Laboratory of Traditional Chinese Medicine & Stress Injury of Shandong Province, Shandong, China
Correspondence Xiaoli Ma, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, China.
Email: [email protected]
Search for more papers by this authorQiang Li
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorJingtan Li
Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
Search for more papers by this authorJingting Wang
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorJing Wang
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorTong Lu
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Intelligent Technology Innovation Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
Search for more papers by this authorYanfei Jia
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorHaiji Sun
Shandong Intelligent Technology Innovation Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
College of Life Science, Shandong Normal University, Shandong, China
Search for more papers by this authorCorresponding Author
Xiaoli Ma
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
Shandong Intelligent Technology Innovation Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
Laboratory of Traditional Chinese Medicine & Stress Injury of Shandong Province, Shandong, China
Correspondence Xiaoli Ma, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, China.
Email: [email protected]
Search for more papers by this author[Correction added on 17 November 2023 after first online publication: Table 1 has been updated.]
Abstract
Evidence has shown a strong relationship between smoking and epithelial mesenchymal transition (EMT). α5-nicotinic acetylcholine receptor (α5-nAChR) contributes to nicotine-induced lung cancer cell EMT. The cytoskeleton-associated protein PLEK2 is mainly involved in cytoskeletal protein recombination and cell stretch migration regulation, which is closely related to EMT. However, little is known about the link between nicotine/α5-nAChR and PLEK2 in lung adenocarcinoma (LUAD). Here, we identified a link between α5-nAChR and PLEK2 in LUAD. α5-nAChR expression was correlated with PLEK2 expression, smoking status and lower survival in vivo. α5-nAChR mediated nicotine-induced PLEK2 expression via STAT3. α5-nAChR/PLEK2 signaling is involved in LUAD cell migration, invasion and stemness. Moreover, PLEK2 was found to interact with CFL1 in nicotine-induced EMT in LUAD cells. Furthermore, the functional link among α5-nAChR, PLEK2 and CFL1 was confirmed in mouse xenograft tissues and human LUAD tissues. These findings reveal a novel α5-nAChR/PLEK2/CFL1 pathway involved in nicotine-induced LUAD progression.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| mc23649-sup-0001-Supp_Figure_1.tif212.5 KB | Supp. Figure 1 The co-immunoprecipitation (Co-IP) assay was used to determine the interaction of PLEK2 and CFL1 in LUAD cells. |
| mc23649-sup-0002-Supp_Figure_2.tif407.3 KB | Supp. Figure 2 CFL1 was regulated by α5-nAChR/STAT3 signaling in LUAD. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71: 209-249.
- 2Friedlaender A, Addeo A, Russo A, Gregorc V, Cortinovis D, Rolfo C. Targeted therapies in early stage NSCLC: hype or hope? Int J Mol Sci. 2020; 21: 6329.
- 3Gallaway MS, Huang B, Chen Q, et al. Smoking and smoking cessation among persons with tobacco- and non-tobacco-associated cancers. J Community Health. 2019; 44: 552-560.
- 4Gu F, Li XF, Xu JF, Gao GH, Wu YF, Zhou CC. Effect of nicotine dependence on quality of life and sleep quality in patients with lung cancer who continue to smoke after diagnosis. J Thorac Dis. 2018; 10: 2583-2589.
- 5Cheng WL, Chen KY, Lee KY, Feng PH, Wu SM. Nicotinic-nAChR signaling mediates drug resistance in lung cancer. J Cancer. 2020; 11: 1125-1140.
- 6Widysanto A, Combest FE, Dhakal A, Saadabadi A. Nicotine Addiction. StatPearls. StatPearls PublishingCopyright © 2022, StatPearls Publishing LLC; 2022.
- 7Zhou W, Zhu W, Tong X, et al. CHRNA5 rs16969968 polymorphism is associated with lung cancer risk: a meta-analysis. The clinical respiratory journal. 2020; 14: 505-513.
- 8Zhang Y, Jia Y, Li P, et al. Reciprocal activation of α5-nAChR and STAT3 in nicotine-induced human lung cancer cell proliferation. J Genet Genomics. 2017; 44: 355-362.
- 9Stephens SH, Hartz SM, Hoft NR, et al. Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking. Genet Epidemiol. 2013; 37: 846-859.
- 10Yang L, Yang Z, Zuo C, et al. Epidemiological evidence for associations between variants in CHRNA genes and risk of lung cancer and chronic obstructive pulmonary disease. Front Oncol. 2022; 12:1001864.
- 11Diabasana Z, Perotin JM, Belgacemi R, et al. Chr15q25 genetic variant rs16969968 alters cell differentiation in respiratory epithelia. Int J Mol Sci. 2021; 22: 6657.
- 12Otsuka Y, Bai X, Tanaka Y, et al. Involvement of interstitial cells of Cajal in nicotinic acetylcholine receptor-induced relaxation of the porcine lower esophageal sphincter. Eur J Pharmacol. 2021; 910:174491.
- 13Chen X, Jia Y, Zhang Y, Zhou D, Sun H, Ma X. α5-nAChR contributes to epithelial-mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer. J Cell Mol Med. 2020; 24: 2497-2506.
- 14Ma X, Jia Y, Zu S, et al. Alpha5 nicotinic acetylcholine receptor mediates nicotine-induced HIF-1α and VEGF expression in non-small cell lung cancer. Toxicol Appl Pharmacol. 2014; 278: 172-179.
- 15Sun HJ, Jia YF, Ma XL. Alpha5 nicotinic acetylcholine receptor contributes to Nicotine-Induced lung cancer development and progression. Front Pharmacol. 2017; 8: 573.
- 16Wang G, Zhou Q, Xu Y, Zhao B. Emerging roles of Pleckstrin-2 beyond cell spreading. Front Cell Dev Biol. 2021; 9:768238.
- 17Wang J, Sun Z, Wang J, et al. Expression and prognostic potential of PLEK2 in head and neck squamous cell carcinoma based on bioinformatics analysis. Cancer Med. 2021; 10: 6515-6533.
- 18Kałuzińska Ż, Kołat D, Bednarek AK, Płuciennik E. PLEK2, RRM2, GCSH: A novel WWOX-Dependent biomarker triad of glioblastoma at the crossroads of cytoskeleton reorganization and metabolism alterations. Cancers. 2021; 13: 2955.
- 19Wang F, Zhang C, Cheng H, et al. TGF-β-induced PLEK2 promotes metastasis and chemoresistance in oesophageal squamous cell carcinoma by regulating LCN2. Cell Death Dis. 2021; 12: 901.
- 20Yang Q, Li K, Li X, Liu J. Identification of key genes and pathways in myeloma side population cells by bioinformatics analysis. Int J Med Sci. 2020; 17: 2063-2076.
- 21Zhang W, Li T, Hu B, Li H. PLEK2 gene upregulation might independently predict shorter Progression-Free survival in lung adenocarcinoma. Technol Cancer Res Treat. 2020; 19:1533033820957030.
- 22Jiang H, Xu S, Chen C. A ten-gene signature-based risk assessment model predicts the prognosis of lung adenocarcinoma. BMC Cancer. 2020; 20: 782.
- 23Cai T, Yao W, Qiu L, Zhu AR, Shi Z, Du Y. PLEK2 promotes the proliferation and migration of non-small cell lung cancer cells in a BRD4-dependent manner. Mol Biol Rep. 2022; 49: 3693-3704.
- 24Shishkin S, Eremina L, Pashintseva N, Kovalev L, Kovaleva M. Cofilin-1 and other ADF/Cofilin superfamily members in human malignant cells. Int J Mol Sci. 2016; 18: 10.
- 25Chang CY, Leu JD, Lee YJ. The actin depolymerizing factor (ADF)/cofilin signaling pathway and DNA damage responses in cancer. Int J Mol Sci. 2015; 16: 4095-4120.
- 26Castro MAA, Dal-Pizzol F, Zdanov S, et al. CFL1 expression levels as a prognostic and drug resistance marker in nonsmall cell lung cancer. Cancer. 2010; 116: 3645-3655.
- 27Chang CY, Chang SL, Leu JD, et al. Comparison of cofilin‑1 and Twist‑1 protein expression in human non‑small cell lung cancer tissues. Oncol Rep. 2019; 42: 805-816.
- 28Müller CB, de Barros RLS, Castro MAA, et al. Validation of cofilin-1 as a biomarker in non-small cell lung cancer: application of quantitative method in a retrospective cohort. J Cancer Res Clin Oncol. 2011; 137: 1309-1316.
- 29Wu DM, Deng SH, Zhou J, et al. PLEK2 mediates metastasis and vascular invasion via the ubiquitin-dependent degradation of SHIP2 in non-small cell lung cancer. Int J Cancer. 2020; 146: 2563-2575.
- 30Jiao Y, Kang G, Pan P, et al. Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via alpha5-nAChR/FHIT pathway. Cellu Mol Life Sci. 2023; 80: 119.
- 31Wu L, Yu Y, Xu L, Wang X, Zhou J, Wang Y. TROY modulates cancer Stem-Like cell properties and gefitinib resistance through EMT signaling in Non-Small cell lung cancer. Front Genet. 2022; 13:881875.
- 32Li X, Ma G, Guo W, et al. Hhex inhibits cell migration via regulating RHOA/CDC42-CFL1 axis in human lung cancer cells. Cell Commun Signaling. 2021; 19: 80.
- 33Trikash I, Kasatkina L, Lykhmus O, Skok M. Nicotinic acetylcholine receptors regulate clustering, fusion and acidification of the rat brain synaptic vesicles. Neurochem Int. 2020; 138:104779.
- 34Wittenberg RE, Wolfman SL, De Biasi M, Dani JA. Nicotinic acetylcholine receptors and nicotine addiction: a brief introduction. Neuropharmacology. 2020; 177:108256.
- 35Jackson A, Grobman B, Krishnan-Sarin S. Recent findings in the pharmacology of inhaled nicotine: preclinical and clinical in vivo studies. Neuropharmacology. 2020; 176:108218.
- 36Li L, Li Z, Lu C, et al. Ibrutinib reverses IL-6-induced osimertinib resistance through inhibition of laminin α5/FAK signaling. Communications biology. 2022; 5: 155.
- 37Ji X, Bossé Y, Landi MT, et al. Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk. Nat Commun. 2018; 9: 3221.
- 38Zhang Q, Jia Y, Pan P, et al. α5-nAChR associated with Ly6E modulates cell migration via TGF-β1/Smad signaling in non-small cell lung cancer. Carcinogenesis. 2022; 43: 393-404.
- 39Jia Y, Zhang Q, Liu Z, et al. The role of α5-nicotinic acetylcholine receptor/NLRP3 signaling pathway in lung adenocarcinoma cell proliferation and migration. Toxicology. 2022; 469:153120.
- 40Shao W, Azam Z, Guo J. To SST. oncogenic potential of PIK3CD in glioblastoma is exerted through cytoskeletal proteins PAK3 and PLEK2. Lab Invest. 2022; 102: 1314-1322.
- 41Zhao B, Mei Y, Cao L, et al. Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms. J Clin Invest. 2018; 128: 125-140.
- 42Shen H, He M, Lin R, et al. PLEK2 promotes gallbladder cancer invasion and metastasis through EGFR/CCL2 pathway. J Exper Clin Canc Res. 2019; 38: 247.
- 43Zhao X, Shu D, Sun W, et al. PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c-Myc-mediated positive feedback loop. Cancer Commun. 2022; 42: 987-1007.
- 44Rajaram P, Chandra P, Ticku S, Pallavi B, Rudresh K, Mansabdar P. Epidermal growth factor receptor: role in human cancer. Indian J Dent Res. 2017; 28: 687-694.
- 45Dempke WCM, Uciechowski P, Fenchel K, Chevassut T. Targeting SHP-1, 2 and SHIP pathways: a novel strategy for cancer treatment? Oncology. 2018; 95: 257-269.
- 46Schaal CM, Bora-Singhal N, Kumar DM, Chellappan SP. Regulation of Sox2 and stemness by nicotine and electronic-cigarettes in non-small cell lung cancer. Mol Cancer. 2018; 17: 149.
- 47Ding K, Jiang X, Ni J, Zhang C, Li A, Zhou J. JWA inhibits nicotine-induced lung cancer stemness and progression through CHRNA5/AKT-mediated JWA/SP1/CD44 axis. Ecotoxicol Environ Safety. 2023; 259:115043.
- 48Mousavi S, Ng O, Saunders JH, Acheson AG, Parsons SL. Study of cofilin 1 gene expression in colorectal cancer. J Gastrointest Oncol. 2018; 9: 791-796.
- 49Guo W, Guo T, Zhou Q, et al. Cofilin-1 promotes fibrocyte differentiation and contributes to pulmonary fibrosis. Biochem Biophys Res Commun. 2021; 565: 43-49.
- 50Tsai CH, Lin LT, Wang CY, et al. Over-expression of cofilin-1 suppressed growth and invasion of cancer cells is associated with up-regulation of let-7 microRNA. Biochimica et Biophysica Acta (BBA). 2015; 1852: 851-861.
- 51Rodríguez-Fernández L, Company S, Zaragozá R, Viña JR, García-Trevijano ER. Cleavage and activation of LIM kinase 1 as a novel mechanism for calpain 2-mediated regulation of nuclear dynamics. Sci Rep. 2021; 11:16339.
- 52Chen L, Cai J, Huang Y, et al. Identification of cofilin-1 as a novel mediator for the metastatic potentials and chemoresistance of the prostate cancer cells. Eur J Pharmacol. 2020; 880:173100.
- 53Wang R, Cai J, Chen K, et al. STAT3-NAV2 axis as a new therapeutic target for rheumatoid arthritis via activating SSH1L/Cofilin-1 signaling pathway. Signal Transduct Target Ther. 2022; 7: 209.
- 54Glogowska A, Thanasupawat T, Beiko J, Pitz M, Hombach-Klonisch S, Klonisch T. Novel CTRP8-RXFP1-JAK3-STAT3 axis promotes Cdc42-dependent actin remodeling for enhanced filopodia formation and motility in human glioblastoma cells. Mol Oncol. 2022; 16: 368-387.
