Ubiquitin–Proteasome Axis,Especially Ubiquitin-Specific Protease-17 ( USP17 ) Gene Family,is a Potential Target for Epithelial–Mesenchymal Transition in High-Grade Serous Ovarian Cancer

Abstract

Objectives:

To investigate gene expression differences and related functions between primary tumor, malignant cells in ascites, and metastatic peritoneal implant in high-grade serous ovarian cancer.

Methods:

Biopsies from primary tumor, peritoneal implant, and ascites were collected from 10 patients operated primarily for high-grade, advanced-staged serous ovarian cancer. Total RNA isolation was performed from collected tissue biopsy and fluid samples, and RNA expression profile was measured. Messenger RNA expression profiles of 3 different groups were compared. Functional analyses of candidate genes were carried out by gene ontology and pathway analysis.

Results:

There were significant differences in the expression of 5 genes between primary tumor and peritoneal implant, 979 genes between primary tumor and malignant cells in ascites, and 649 genes between peritoneal implant and malignant cells in ascites. Three commonly enriched gene ontology functions between “primary tumor and malignant cells in the ascites” and “peritoneal implant and malignant cells in the ascites” were protein deubiquitination, ubiquitin-dependent protein catabolism, and apoptotic processes. All genes related to these functions belonged to USP17 gene family.

Conclusion:

Gene expression difference between primary tumor and the peritoneal implant is not as much as the difference between primary tumor and free cells in the ascites. These results show that malignant cells in the ascites return into its genetic origin after they invade on the peritoneum. Significantly increased expression of DUB-enzyme genes, SNAR gene family, and ribosomal pathway genes in epithelial–mesenchymal transition suggests that this regulation is ubiquitin–proteasome dependent. Especially, this is the first study that offers USP17 as a potential target for epithelial–mesenchymal transition.

Keywords

ovarian cancer serous microarray epithelial–mesenchymal transition deubiquitination ubiquitin–proteasome pathway

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References

Ferlay

Autier

Boniol

Heanue

Colombet

Boyle

. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007;18(3):581–592.

Kurman

Shih

IeM

. Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol. 2008;27(2):151–160.

Chi

Eisenhauer

Zivanovic

. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol. 2009;114(1):26–31.

Vergote

Amant

Kristensen

Ehlen

Reed

Casado

. Primary surgery or neoadjuvant chemotherapy followed by interval debulking surgery in advanced ovarian cancer. Eur J Cancer. 2011;47(suppl 3):88–92.

SEER 9 Incidence & U.S. Mortality 1975-2014. http://seer.cancer.gov/statfacts/html/ovary.html Accessed 2008-2014.

Jemal

Siegel

Ward

. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71–96.

Pfisterer

Harter

Canzler

; AGO Ovarian Committee; AGO Ovarian Cancer Study Group (AGO-OVAR) . The role of surgery in recurrent ovarian cancer. Int J Gynecol Cancer. 2005;15(suppl 3):195–198.

Kalluri

Neilson

. Epithelial–mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003;112(12):1776–1784.

Kalluri

Weinberg

. The basics of epithelial–mesenchymal transition. J Clin Invest. 2009;119(6):1420–1428.

10.

Yoshida

Furukawa

Haruta

. Expression profiles of genes involved in poor prognosis of epithelial ovarian carcinoma: a review. Int J Gynecol Cancer. 2009;19(6):992–997.

11.

Lancaster

Dressman

Clarke

. Identification of genes associated with ovarian cancer metastasis using microarray expression analysis. Int J Gynecol Cancer. 2006;16(5):1733–1745.

12.

Welsh

Zarrinkar

Sapinoso

. Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. Proc Natl Acad Sci U S A. 2001;98(3):1176–1181.

13.

De Smet

Pochet

Engelen

. Predicting the clinical behavior of ovarian cancer from gene expression profiles. Int J Gynecol Cancer. 2006;16(suppl 1):147–151.

14.

Koh

. Preparation of cells for microscopy using cytospin. Methods Enzymol. 2013;533:235–240.

15.

Wen

Lin

Kuo

Chen

Chai

. Cell transfer technique for constructing cytological microarrays for immunocytochemical analysis. Cytopathology. 2017;28(2):157–163.

16.

Sherman

Huang da

Tan

. DAVID Knowledgebase: a gene-centered database integrating heterogeneous gene annotation resources to facilitate high-throughput gene functional analysis. BMC Bioinformatics. 2007;8:426.

17.

Szklarczyk

Franceschini

Wyder

. STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:447–452.

18.

Lengyel

. Ovarian cancer development and metastasis. Am J Pathol. 2010;177(3):1053–1064.

19.

Davidson

Tropé

Reich

. Epithelial–mesenchymal transition in ovarian carcinoma. Front Oncol. 2012;2:33.

20.

Strauss

Liu

. Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. PLos One. 2011;6(1):e16186.

21.

Klymenko

Kim

Stack

. Complex determinants of epithelial: mesenchymal phenotypic plasticity in ovarian cancer. Cancers (Basel). 2017;9(8):E104.

22.

Wang

Chang

. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43(6):904–914.

23.

Lee

Park

Kim

. Biological function of long noncoding RNA snaR in HER2-positive breast cancer cells. Tumour Biol. 2017;39(6):1010428317707374.

24.

Parrott

Tsai

Batchu

. The evolution and expression of the snaR family of small non-coding RNAs. Nucleic Acids Res. 2011;39(4):1485–1500.

25.

Lee

Jung

Chae

. Long Noncoding RNA snaR regulates proliferation, migration and invasion of triple-negative breast cancer cells. Anticancer Res. 2016;36(12):6289–6295.

26.

Lou

. Differential distribution of U6 (RNU6-1) expression in human carcinoma tissues demonstrates the requirement for caution in the internal control gene selection for microRNA quantification. Int J Mol Med. 2015;36(5):1400–1408.

27.

Xiao-Jie

Ai-Mei

Li-Juan

Jiang

. Pseudogene in cancer: real functions and promising signature. J Med Genet. 2015;52(1):17–24.

28.

Chen

OuYang

Liu

. Vault RNAs partially induces drug resistance of human tumor cells MCF-7 by binding to the RNA/DNA-binding protein PSF and inducing oncogene GAGE6. PLos One. 2018;13(1):e0191325.

29.

Amort

Nachbauer

Tuzlak

. Expression of the vault RNA protects cells from undergoing apoptosis. Nat Commun. 2015;6:7030.

30.

. MCAM is a novel metastasis marker and regulates spreading, apoptosis and invasion of ovarian cancer cells. Tumour Biol. 2012;33(5):1619–1628.

31.

Davis

Simeonov

. Ubiquitin-specific proteases as druggable targets. Drug Target Rev. 2015;2(3):60–64.

32.

Burrows

Kelvin

McFarlane

. USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity. J Biol Chem. 2009;284(14):9587–9595.

33.

Burrows

Scott

Johnston

. The DUB/USP17 deubiquitinating enzymes: a gene family within a tandemly repeated sequence, is also embedded within the copy number variable beta-defensin cluster. BMC Genomics. 2010;11:250.

34.

D’Arcy

Wang

Linder

. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther. 2015;147:32–54.

35.

Pickart

Eddins

. Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta. 2004;1695(1-3):55–72.

36.

Abdul-Rehman

Kristariyanto

Choi

. MINDY-1 is a member of an evolutionarily conserved and structurally distinct new family of deubiquitinating enzymes. Mol Cell. 2016;63(1):146–155.

37.

Zhou

Chen

Wan

. Emerging role of DUBs in tumor metastasis and apoptosis: therapeutic implication. Pharmacol Ther. 2017;177:96–107.

38.

Xing

Guo

. Ubiquitin-Specific protease 4-mediated deubiquitination and stabilization of prl-3 is required for potentiating colorectal oncogenesis. Cancer Res. 2016;76(1):83–95.

39.

Yang

Zhang

Liu

. USP22 promotes tumor progression and induces epithelial–mesenchymal transition in lung adenocarcinoma. Lung Cancer. 2015;88(3):239–245.

40.

Jensen

Proctor

Marquis

. Bap1: a novel ubiquitin hydrolase which binds to the brca1 ring finger and enhances brca1-mediated cell growth suppression. Oncogene. 1998;16(9):1097–1112.

41.

Rao

Ding

. Ubiquitin pathway and ovarian cancer. Curr Oncol. 2012;19(6):324–328.

42.

Wang

Zhong

. Ubiquitin-specific protease 14 (USP14) regulates cellular proliferation and apoptosis in epithelial ovarian cancer. Med Oncol. 2015;32(1):379.

43.

Burrows

McGrattan

Rascle

. DUB-3, a cytokine-inducible deubiquitinating enzyme that blocks proliferation. J Biol Chem. 2004;279(14):13993–4000.

44.

de la Vega

Burrows

McFarlane

. The deubiquitinating enzyme USP17 blocks N-Ras membrane trafficking and activation but leaves K-Ras unaffected. J Biol Chem. 2010;285(16):12028–12036.

45.

McFarlane

Paul

. The deubiquitinating enzyme USP17 is associated with non-small cell lung cancer (NSCLC) recurrence and metastasis. Oncotarget. 2013;4(10):1836–1843.

46.

Zhang

Yuan

Zheng

. Suppression of ubiquitin-specific peptidase 17 (USP17) inhibits tumorigenesis and invasion in non-small cell lung cancer cells. Oncol Res. 2016;24(4):263–269.

47.

Song

Liu

. USP17 is upregulated in osteosarcoma and promotes cell proliferation, metastasis, and epithelial–mesenchymal transition through stabilizing SMAD4. Tumour Biol. 2017;39(7): doi:10.1177/1010428317717138

48.

Wang

Stearns

. RPS2: a novel therapeutic target in prostate cancer. J Exp Clin Cancer Res. 2009;28:6.

49.

Wei

Ding

Wei

. Ribosomal protein L34 promotes the proliferation, invasion and metastasis of pancreatic cancer cells. Oncotarget. 2016;7(51):85259–85272.

50.

Wei

Wang

. Ribosomal L22-like1 (RPL22L1) promotes ovarian cancer metastasis by inducing epithelial-to-mesenchymal transition. PLos One. 2015;10(11):e0143659.

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