MID1-PP2A Complex Functions As New Insights in Human Lung Adenocarcinoma

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2018 Feb 17

PMID 29450633

Citations 11

Authors

Lin Zhang

Junyao Li

Xuejiao Lv

Tingting Guo

Wei Li

Jie Zhang

Affiliations

Soon will be listed here.

Abstract

Purpose: MID1 is an E3 ubiquitin ligase that was first found in Opitz G/BBB syndrome, but there has been little research into its role in lung diseases. We have found an accumulating evidence that indicates the MID1-PP2A complex plays a role in asthma and contributes to inflammation, but its roles in lung adenocarcinoma are unclear. This study aimed at evaluating the function of MID1-PP2A complex in human lung adenocarcinoma.

Methods: We used western blot, ELISA and real-time quantitative PCR to detect the protein and mRNA levels of MID1 and PP2A in A549, H1975, and H1650 lung adenocarcinoma cell lines compared with the human bronchial epithelial cell line BEAS-2B. Additionally, we used IHC, ELISA and real-time quantitative PCR to dectect MID1 and PP2A levels in 30-paired lung adenocarcinoma tissues. We also detected apoptosis, proliferation and cell cycle-related protein expression after silencing MID1 and activing PP2A.

Results: Our data show that MID1 was significantly upregulated in 30-paired lung adenocarcinoma tissues, and in A549, H1975 and H1650 cell lines compared with BEAS-2B. PP2A showed the opposite results. Furthermore, both upregulated MID1 and downregulated PP2A were correlated with age, but not sex, TNM stage or smoking history. In vitro experiments showed that PP2A was upregulated in lung adenocarcinoma cell lines that were transfected with MID1-siRNA, suggesting MID1 negatively regulates PP2A in lung adenocarcinoma. We also found that silencing MID1 expression or activating PP2A induced apoptosis, proliferation and cell cycle arrest.

Conclusions: We demonstrated that the MID1-PP2A complex plays an important role in lung adenocarcinoma, influencing cell cycle progression, proliferation and apoptosis. Our findings showed a novel molecular mechanism of lung tumorigenesis that may provide new insights for anti-tumor therapies.

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References

Li J, Yang M, Li P, Su Z, Gao P, Zhang J . Idiopathic pulmonary fibrosis will increase the risk of lung cancer. Chin Med J (Engl). 2014; 127(17):3142-9. View

Krauss S, Griesche N, Jastrzebska E, Chen C, Rutschow D, Achmuller C . Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1-PP2A protein complex. Nat Commun. 2013; 4:1511. DOI: 10.1038/ncomms2514. View

Mane D, Kale A, Belaldavar C . Validation of immunoexpression of tenascin-C in oral precancerous and cancerous tissues using ImageJ analysis with novel immunohistochemistry profiler plugin: An immunohistochemical quantitative analysis. J Oral Maxillofac Pathol. 2017; 21(2):211-217. PMC: 5596670. DOI: 10.4103/jomfp.JOMFP_234_16. View

Hao J, Chen J, Sui H, Si-Ma X, Li G, Liu C . A five-gene signature as a potential predictor of metastasis and survival in colorectal cancer. J Pathol. 2010; 220(4):475-89. DOI: 10.1002/path.2668. View

Cagnol S, Chambard J . ERK and cell death: mechanisms of ERK-induced cell death--apoptosis, autophagy and senescence. FEBS J. 2009; 277(1):2-21. DOI: 10.1111/j.1742-4658.2009.07366.x. View

Cristobal I, Manso R, Rincon R, Carames C, Senin C, Borrero A . PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential. Mol Cancer Ther. 2014; 13(4):938-47. DOI: 10.1158/1535-7163.MCT-13-0150. View

Grivennikov S, Greten F, Karin M . Immunity, inflammation, and cancer. Cell. 2010; 140(6):883-99. PMC: 2866629. DOI: 10.1016/j.cell.2010.01.025. View

Siegel R, Miller K, Jemal A . Cancer Statistics, 2017. CA Cancer J Clin. 2017; 67(1):7-30. DOI: 10.3322/caac.21387. View

Robin N, Feldman G, ARONSON A, Mitchell H, Weksberg R, Leonard C . Opitz syndrome is genetically heterogeneous, with one locus on Xp22, and a second locus on 22q11.2. Nat Genet. 1995; 11(4):459-61. DOI: 10.1038/ng1295-459. View

10.

Watkins G, Wang N, Mazalouskas M, Gomez R, Guthrie C, Kraemer B . Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit α4, altering PP2A stability and microtubule-associated protein phosphorylation. J Biol Chem. 2012; 287(29):24207-15. PMC: 3397847. DOI: 10.1074/jbc.M112.368613. View

11.

Collison A, Li J, Pereira de Siqueira A, Zhang J, Toop H, Morris J . Tumor necrosis factor-related apoptosis-inducing ligand regulates hallmark features of airways remodeling in allergic airways disease. Am J Respir Cell Mol Biol. 2014; 51(1):86-93. DOI: 10.1165/rcmb.2013-0490OC. View

12.

Kloeker S, Reed R, McConnell J, Chang D, Tran K, Westphal R . Parallel purification of three catalytic subunits of the protein serine/threonine phosphatase 2A family (PP2A(C), PP4(C), and PP6(C)) and analysis of the interaction of PP2A(C) with alpha4 protein. Protein Expr Purif. 2003; 31(1):19-33. DOI: 10.1016/s1046-5928(03)00141-4. View

13.

Collison A, Hatchwell L, Verrills N, Wark P, Pereira de Siqueira A, Tooze M . The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity. Nat Med. 2013; 19(2):232-7. DOI: 10.1038/nm.3049. View

14.

Arigoni M, Barutello G, Riccardo F, Ercole E, Cantarella D, Orso F . miR-135b coordinates progression of ErbB2-driven mammary carcinomas through suppression of MID1 and MTCH2. Am J Pathol. 2013; 182(6):2058-70. DOI: 10.1016/j.ajpath.2013.02.046. View

15.

Krauss S, Foerster J, Schneider R, Schweiger S . Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3. Cancer Res. 2008; 68(12):4658-65. DOI: 10.1158/0008-5472.CAN-07-6174. View

16.

Bishop J . Molecular themes in oncogenesis. Cell. 1991; 64(2):235-48. DOI: 10.1016/0092-8674(91)90636-d. View

17.

Grech G, Baldacchino S, Saliba C, Grixti M, Gauci R, Petroni V . Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutic options. Tumour Biol. 2016; 37(9):11691-11700. DOI: 10.1007/s13277-016-5145-4. View

18.

Quaderi N, Schweiger S, Gaudenz K, Franco B, Rugarli E, Berger W . Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat Genet. 1997; 17(3):285-91. DOI: 10.1038/ng1197-285. View

19.

Kohler A, Demir U, Kickstein E, Krauss S, Aigner J, Aranda-Orgilles B . A hormone-dependent feedback-loop controls androgen receptor levels by limiting MID1, a novel translation enhancer and promoter of oncogenic signaling. Mol Cancer. 2014; 13:146. PMC: 4074869. DOI: 10.1186/1476-4598-13-146. View

20.

Lv X, Du Y, Hao Y, Su Z, Zhang L, Zhao L . RNA-binding motif protein 5 inhibits the proliferation of cigarette smoke-transformed BEAS-2B cells through cell cycle arrest and apoptosis. Oncol Rep. 2016; 35(4):2315-27. DOI: 10.3892/or.2016.4551. View