LACTB suppresses carcinogenesis in lung cancer and regulates the EMT pathway

Xu,Yihui; Shi,Hubo; Wang,Min; Huang,Ping; Xu,Mingjie; Han,Shuyi; Li,Huanjie; Wang,Yunshan

doi:10.3892/etm.2022.11172

LACTB suppresses carcinogenesis in lung cancer and regulates the EMT pathway

Authors:
- Yihui Xu
- Hubo Shi
- Min Wang
- Ping Huang
- Mingjie Xu
- Shuyi Han
- Huanjie Li
- Yunshan Wang
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Affiliations: Medical Research and Laboratory Diagnostic Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, P.R. China, Department of Thoracic Surgery, Shangdong Public Health Clinical Center, Jinan, Shandong 250102, P.R. China, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: January 28, 2022 https://doi.org/10.3892/etm.2022.11172
Article Number: 247
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer causes thousands of deaths worldwide every year, and present therapeutics show little benefit for advanced‑stage patients. Researchers do not know why and how lung cancer begins. Lactamase β (LACTB) is a tumor‑suppressor in some cancers. However, its role in lung cancer is unknown. By analyzing the TCGA database and Kaplan‑Meier Plotter database, LACTB was found to be downregulated in lung cancer tissues but the methylation level was increased. Patients with high LACTB expression exhibited improved survival. Then, in vitro assays demonstrated that LACTB overexpression inhibited cell migration and invasion, and induced apoptosis in H1299 and H1975 cells. Knockdown of LACTB caused the reverse effects. Moreover, a much higher apoptotic rate and more potent inhibitory effects on H1299 and H1975 cells were obtained when LACTB was combined with docetaxel. In addition, members of the epithelial‑mesenchymal transition (EMT) signaling pathway were assessed using western blot analysis. The expression of E‑cadherin was decreased while levels of N‑cadherin and vimentin were increased after knockdown of LACTB in lung cancer cells. By contrast, overexpression of LACTB increased the level of E‑cadherin but decreased N‑cadherin and vimentin. Therefore, LACTB is a tumor suppressor in lung cancer that inhibits cell migration and invasion and induces cell apoptosis. Meanwhile, LACTB was found to strengthen the anticancer role of docetaxel and to suppress the EMT pathway in lung cancer.

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1	Siegel RL, Miller KD, Fuchs HE and Jemal A: Cancer statistics, 2021. CA Cancer J Clin. 71:7–33. 2021.PubMed/NCBI View Article : Google Scholar
2	Wu F, Wang L and Zhou C: Lung cancer in China: Current and prospect. Curr Opin Oncol. 33:40–46. 2021.PubMed/NCBI View Article : Google Scholar
3	Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ, Yi-Long W and Paz-Ares L: Lung cancer: current therapies and new targeted treatments. Lancet. 389:299–311. 2017.PubMed/NCBI View Article : Google Scholar
4	de Sousa VM and Carvalho L: Heterogeneity in lung cancer. Pathobiology. 85:96–107. 2018.PubMed/NCBI View Article : Google Scholar
5	Bai X, Meng L, Sun H, Li Z, Zhang X and Hua S: MicroRNA-196b inhibits cell growth and metastasis of lung cancer cells by targeting Runx2. Cell Physiol Biochem. 43:757–767. 2017.PubMed/NCBI View Article : Google Scholar
6	Devlin JR and Verschuren EW: More than a tumor suppressor: E-Cadherin loss drives lung cancer metastasis. Am J Respir Cell Mol Biol. 59:141–142. 2018.PubMed/NCBI View Article : Google Scholar
7	Ma Y, Wang L, He F, Yang J, Ding Y, Ge S, Fan X, Zhou Y, Xu X and Jia R: LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction. Cancer Lett. 506:67–82. 2021.PubMed/NCBI View Article : Google Scholar
8	Li HT, Dong DY, Liu Q, Xu YQ and Chen L: Overexpression of LACTB, a mitochondrial protein that inhibits proliferation and invasion in glioma cells. Oncol Res. 27:423–429. 2019.PubMed/NCBI View Article : Google Scholar
9	Al-Ostoot FH, Salah S, Khamees HA and Khanum SA: Tumor angiogenesis: Current challenges and therapeutic opportunities. Cancer Treat Res Commun. 28(100422)2021.PubMed/NCBI View Article : Google Scholar
10	Zeng K, Chen X, Hu X, Liu X, Xu T, Sun H, Pan Y, He B and Wang S: LACTB, a novel epigenetic silenced tumor suppressor, inhibits colorectal cancer progression by attenuating MDM2-mediated p53 ubiquitination and degradation. Oncogene. 37:5534–5551. 2018.PubMed/NCBI View Article : Google Scholar
11	Peng LX, Wang MD, Xie P, Yang JP, Sun R, Zheng LS, Mei Y, Meng DF, Peng XS, Lang YH, et al: LACTB promotes metastasis of nasopharyngeal carcinoma via activation of ERBB3/EGFR-ERK signaling resulting in unfavorable patient survival. Cancer Lett. 498:165–177. 2021.PubMed/NCBI View Article : Google Scholar
12	Xie J, Peng Y, Chen X, Li Q, Jian B, Wen Z and Liu S: LACTB mRNA expression is increased in pancreatic adenocarcinoma and high expression indicates a poor prognosis. PLoS One. 16(e0245908)2021.PubMed/NCBI View Article : Google Scholar
13	Vasan N, Baselga J and Hyman DM: A view on drug resistance in cancer. Nature. 575:299–309. 2019.PubMed/NCBI View Article : Google Scholar
14	Yang F, Yan Z, Nie W, Cheng X, Liu Z, Wang W, Shao C, Fu G and Yu Y: LACTB induced apoptosis of oxaliplatin-resistant gastric cancer through regulating autophagy-mediated mitochondrial apoptosis pathway. Am J Transl Res. 13:601–616. 2021.PubMed/NCBI
15	Dibgre A and Weinberg RA: New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 20:69–84. 2019.PubMed/NCBI View Article : Google Scholar
16	Jiang L, Huang J, Hu Y, Lu P, Luo Q and Wang L: Gli promotes tumor progression through regulating epithelial-mesenchymal transition in non-small-cell lung cancer. J Cardiothorac Surg. 15(18)2020.PubMed/NCBI View Article : Google Scholar
17	Xu W, Yu M, Qin J, Luo Y and Zhong M: LACTB regulates PIK3R3 to promote autophagy and inhibit EMT and proliferation through the PI3K/AKT/mTOR signaling pathway in colorectal cancer. Cancer Manag Res. 12:5181–5200. 2020.PubMed/NCBI View Article : Google Scholar
18	Livak KJ and Schmitten 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
19	Tomczak K, Czerwińska P and Wiznerowicz M: The cancer genome atlas (TCGA): An immeasurable source of knowledge. Contemp Oncol (Pozn). 19:A68–A77. 2015.PubMed/NCBI View Article : Google Scholar
20	Heberle E and Bardet AF: Sensitivity of transcription factors to DNA methylation. Essays Biochem. 63:727–741. 2019.PubMed/NCBI View Article : Google Scholar
21	Xue C, He Y, Zhu W, Chen X, Yu Y, Hu Q, Chen J, Liu L, Ren F, Ren Z, et al: Low expression of LACTB promotes tumor progression and predicts poor prognosis in hepatocellular carcinoma. Am J Transl Res. 10:4152–4162. 2018.PubMed/NCBI
22	Senga SS and Grose RP: Hallmarks of cancer-the new testament. Open Biol. 11(200358)2021.PubMed/NCBI View Article : Google Scholar
23	Mohammadian J, Sabzichi M, Molavi O, Shanehbandi D and Samadi N: Combined treatment with stattic and docetaxel alters the Bax/Bcl-2 gene expression ratio in human prostate cancer cells. Asian Pac J Cancer Prev. 17:5031–5035. 2016.PubMed/NCBI View Article : Google Scholar
24	Zhang J, Wang J, Wong YK, Sun X, Chen Y, Wang L, Yang L, Lu L, Shen HM and Huang D: Docetaxel enhances lysosomal function through TFEB activation. Cell Death Dis. 9(614)2018.PubMed/NCBI View Article : Google Scholar
25	Colli LM, Machiela MJ, Zhang H, Myers TA, Jessop L, Delattre O, Yu K and Chanock SJ: Landscape of combination immunotherapy and targeted therapy to improve cancer management. Cancer Res. 77:3666–3671. 2017.PubMed/NCBI View Article : Google Scholar
26	Asna N, Livoff A, Batash R, Debbi R, Schaffer P, Rivkind T and Schaffer M: Radiation therapy and immunotherapy-a potential combination in cancer treatment. Curr Oncol. 25:e454–e460. 2018.PubMed/NCBI View Article : Google Scholar
27	Pastushenko I and Blanpain C: EMT transition states during tumor progression and metastasis. Trends Cell Biol. 29:212–226. 2019.PubMed/NCBI View Article : Google Scholar
28	Tulchinsky E, Demidov O, Kriajeska M, Barlev NA and Imyanitov E: EMT: A mechanism for escape from EGFR-targeted therapy in lung cancer. Biochim Biophys Acta Rev Cancer. 1871:29–39. 2019.PubMed/NCBI View Article : Google Scholar
29	Chae YK, Chang S, Ko T, Anker J, Agte S, Iams W, Choi WM, Lee K and Cruz M: Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC). Sci Rep. 8(2918)2018.PubMed/NCBI View Article : Google Scholar
30	Ribatti D, Tamma R and Annese T: Epithelial-mesenchymal transition in cancer: A historical overview. Transl Oncol. 13(100773)2020.PubMed/NCBI View Article : Google Scholar
31	Villarejo A, Cortés-Cabrera A, Molina-Ortiz P, Portillo F and Cano A: Differential role of Snail1 and Snail2 zinc fingers in E-cadherin repression and epithelial to mesenchymal transition. J Biol Chem. 289:930–941. 2014.PubMed/NCBI View Article : Google Scholar
32	Shen W, Pang H, Liu J, Zhou J, Zhang F and Liu L, Ma N, Zhang N, Zhang H and Liu L: Epithelial-mesenchymal transition contributes to docetaxel resistance in human non-small cell lung cancer. Oncol Res. 22:47–55. 2014.PubMed/NCBI View Article : Google Scholar