Derlin1 Functions As an Oncogene in Cervical Cancer Via AKT/mTOR Signaling Pathway

Overview

Journal Biol Res

Specialty Biology

Date 2019 Feb 28

PMID 30808417

Citations 4

Authors

Ling Li

Ming Liu

Zhihu Zhang

Wei Zhang

Naifu Liu

Xiugui Sheng

Ping Wei

Affiliations

Soon will be listed here.

Abstract

Background: Cervical cancer (CC) ranks third in the morbidity and mortality of female cancer around the world. Derlin1 has been found to be overexpressed in several human cancers. However, it is still unclear about its roles in CC. The research aims to explore the relationship between Derlin1 and CC.

Methods: We purchased a human CC tissues microarray, which contained CC tissues and corresponding para-cancerous tissues from 93 patients with primary cervical squamous cell carcinoma. Immunohistochemical staining was used to confirm the expression of Derlin1 in these tissues. And we detected the differential expression of Derlin1 in cervical cancer cell lines and normal cervical epithelial cells (H8). Further, the cervical cancer cell lines SiHa and C33A were used as an in vitro model, which was down-regulated the expression of Derlin1 using siRNA interference technology. The effects of Derlin1 down-regulating in CC cell lines on cell proliferation and migration were detected by CCK8 assay and transwell assay, respectively. The effect of Derlin1 down-regulating on apoptosis was analyzed by flow cytometry, and apoptosis-related proteins were detected using western blotting. In-depth mechanisms were studied using western blotting. In addition, the effects of Derlin1 up-regulating in normal cervical epithelial cells also were exposed.

Results: Derlin1 was significantly elevated in CC tissues (81.7%, 76/93), and the expression of Derlin1 was positively correlated with the tumor size, pathological grade, and lymph node metastasis in CC patients. And Derlin1 was high expressed in cervical cancer cell lines compared to H8 cells. Knockdown of Derlin1 in cervical cancer cell lines inhibited cell proliferation and migration. Moreover, knockdown of Derlin1 induced apoptosis and affected the expression of apoptosis-related proteins, including Bcl-2, Bax, Bim, caspase3 and caspase9. Further experiments showed that AKT/mTOR signal pathway might be involve in this processes that knockdown of Derlin1 inhibited the expression of p-AKT and p-mTOR. Over-expression of Derlin1 in H8 cells promoted cell proliferation and migration via up-regulated the expression of p-AKT and p-mTOR.

Conclusion: Derlin1 is an oncogene in CC via AKT/mTOR pathway. It might be a potential therapeutic target for CC.

Citing Articles

Hypothalamic SLC7A14 accounts for aging-reduced lipolysis in white adipose tissue of male mice.

Jiang X, Liu K, Luo P, Li Z, Xiao F, Jiang H Nat Commun. 2024; 15(1):7948.

PMID: 39261456 PMC: 11391058. DOI: 10.1038/s41467-024-52059-1.

TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression.

Zhang T, Liao L, Yang S, Huang M, Zhang Y, Deng L Autophagy. 2022; 19(3):805-821.

PMID: 35920704 PMC: 9980475. DOI: 10.1080/15548627.2022.2103992.

Regulation of miR-30b in cancer development, apoptosis, and drug resistance.

Fu Z, Chen Y, Xu Y, Lin M, Wen H, Chen Y Open Life Sci. 2022; 17(1):102-106.

PMID: 35291564 PMC: 8886600. DOI: 10.1515/biol-2022-0017.

Functionalized selenium nanoparticles for targeted siRNA delivery silence Derlin1 and promote antitumor efficacy against cervical cancer.

Xia Y, Tang G, Wang C, Zhong J, Chen Y, Hua L Drug Deliv. 2019; 27(1):15-25.

PMID: 31830840 PMC: 6968560. DOI: 10.1080/10717544.2019.1667452.

References

Hockel M, Vaupel P . Biological consequences of tumor hypoxia. Semin Oncol. 2001; 28(2 Suppl 8):36-41. View

Mukherjee G, Freeman A, MOORE R, Kumaraswamy , Devi K, Morris L . Biologic factors and response to radiotherapy in carcinoma of the cervix. Int J Gynecol Cancer. 2001; 11(3):187-93. DOI: 10.1046/j.1525-1438.2001.01014.x. View

Huh W, Gomez-Navarro J, Arafat W, Xiang J, Mahasreshti P, Alvarez R . Bax-induced apoptosis as a novel gene therapy approach for carcinoma of the cervix. Gynecol Oncol. 2001; 83(2):370-7. DOI: 10.1006/gyno.2001.6403. View

Breckenridge D, Germain M, Mathai J, Nguyen M, Shore G . Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene. 2003; 22(53):8608-18. DOI: 10.1038/sj.onc.1207108. View

Le Q, Denko N, Giaccia A . Hypoxic gene expression and metastasis. Cancer Metastasis Rev. 2004; 23(3-4):293-310. DOI: 10.1023/B:CANC.0000031768.89246.d7. View

Schroder M, Kaufman R . ER stress and the unfolded protein response. Mutat Res. 2004; 569(1-2):29-63. DOI: 10.1016/j.mrfmmm.2004.06.056. View

Karbowski M, Norris K, Cleland M, Jeong S, Youle R . Role of Bax and Bak in mitochondrial morphogenesis. Nature. 2006; 443(7112):658-62. DOI: 10.1038/nature05111. View

Wang J, Hua H, Ran Y, Zhang H, Liu W, Yang Z . Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis. Breast Cancer Res. 2008; 10(1):R7. PMC: 2374959. DOI: 10.1186/bcr1849. View

Hara T, Omura-Minamisawa M, Kang Y, Cheng C, Inoue T . Flavopiridol potentiates the cytotoxic effects of radiation in radioresistant tumor cells in which p53 is mutated or Bcl-2 is overexpressed. Int J Radiat Oncol Biol Phys. 2008; 71(5):1485-95. DOI: 10.1016/j.ijrobp.2008.03.039. View

10.

Berman S, Chen Y, Qi B, McCaffery J, Rucker 3rd E, Goebbels S . Bcl-x L increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol. 2009; 184(5):707-19. PMC: 2686401. DOI: 10.1083/jcb.200809060. View

11.

Shin H, Kim J, Hampson L, Pyo H, Baek H, Roberts S . Human papillomavirus 16 E6 increases the radiosensitivity of p53-mutated cervical cancer cells, associated with up-regulation of aurora A. Int J Radiat Biol. 2010; 86(9):769-79. DOI: 10.3109/09553002.2010.484477. View

12.

Biewenga P, van der Velden J, Mol B, Stalpers L, Schilthuis M, van der Steeg J . Prognostic model for survival in patients with early stage cervical cancer. Cancer. 2010; 117(4):768-76. DOI: 10.1002/cncr.25658. View

13.

Schiffman M, Wentzensen N, Wacholder S, Kinney W, Gage J, Castle P . Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst. 2011; 103(5):368-83. PMC: 3046952. DOI: 10.1093/jnci/djq562. View

14.

Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin. 2011; 61(2):69-90. DOI: 10.3322/caac.20107. View

15.

Hasty P, Christy B . p53 as an intervention target for cancer and aging. Pathobiol Aging Age Relat Dis. 2013; 3. PMC: 3794078. DOI: 10.3402/pba.v3i0.22702. View

16.

Vici P, Mariani L, Pizzuti L, Sergi D, Di Lauro L, Vizza E . Emerging biological treatments for uterine cervical carcinoma. J Cancer. 2014; 5(2):86-97. PMC: 3909763. DOI: 10.7150/jca.7963. View

17.

Xu L, Wang Z, Xu D, Lin G, Li D, Wan T . Expression of Derlin-1 and its effect on expression of autophagy marker genes under endoplasmic reticulum stress in lung cancer cells. Cancer Cell Int. 2014; 14:50. PMC: 4061450. DOI: 10.1186/1475-2867-14-50. View

18.

Liang C, Chang Y, Chang H, Wang C, Hung Y, Lin Y . Derlin-1 regulates mutant VCP-linked pathogenesis and endoplasmic reticulum stress-induced apoptosis. PLoS Genet. 2014; 10(9):e1004675. PMC: 4177747. DOI: 10.1371/journal.pgen.1004675. View

19.

Li D, Shi M, Ji H, Chen G, Jiang H, Wang Z . MicroRNA-181d is a tumor suppressor in human esophageal squamous cell carcinoma inversely regulating Derlin-1. Oncol Rep. 2016; 36(4):2041-8. DOI: 10.3892/or.2016.5028. View

20.

Wu Z, Wang C, Zhang Z, Liu W, Xu H, Wang H . High Expression of Derlin-1 Is Associated with the Malignancy of Bladder Cancer in a Chinese Han Population. PLoS One. 2016; 11(12):e0168351. PMC: 5158059. DOI: 10.1371/journal.pone.0168351. View