Regulation of the expression of CLU isoforms in endometrial proliferative diseases

Fuzio,Paolo; Valletti,Alessio; Napoli,Anna; Napoli,Grazia; Cormio,Gennaro; Selvaggi,Luigi; Liuni,Sabino; Pesole,Graziano; Maiorano,Eugenio; Perlino,Elda

doi:10.3892/ijo.2013.1894

Regulation of the expression of CLU isoforms in endometrial proliferative diseases

Authors:
- Paolo Fuzio
- Alessio Valletti
- Anna Napoli
- Grazia Napoli
- Gennaro Cormio
- Luigi Selvaggi
- Sabino Liuni
- Graziano Pesole
- Eugenio Maiorano
- Elda Perlino
View Affiliations

Affiliations: Institute of Biomedical Technologies, ITB-CNR, I-70126 Bari, Italy, Institute of Biomembranes and Bioenergetics, IBBE‑CNR, I-70126 Bari, Italy, Interdisciplinary Department of Medicine, University of Bari ‘Aldo Moro’, I-70124 Bari, Italy, Department of Pathological Anatomy and Genetics, Hospital of SS. Annunziata, I-74100 Taranto, Italy, Department of Biomedical Sciences and Human Oncology, DIMO, University of Bari ‘Aldo Moro’, I-70124 Bari, Italy
Published online on: April 11, 2013 https://doi.org/10.3892/ijo.2013.1894
Pages: 1929-1944

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Clusterin (CLU) is a nearly ubiquitous multifunctional protein synthesized in different functionally divergent isoforms, sCLU and nCLU, playing a crucial role by keeping a balance between cell proliferation and death. Studying in vivo CLU expression we found a higher mRNA expression both in neoplastic and hyperplastic tissues in comparison to normal endometria; in particular, by RT-qPCR we demonstrated an increase of the specific sCLU isoform in the neoplastic and hyperplastic endometrial diseases. On the contrary, no CLU increase was detected at the protein level. The CLU gene transcriptional activity was upregulated in the hyperplastic and neoplastic tissues, indicating the existence of a fine post-transcriptional regulation of CLU expression possibly responsible for the protein decrease in the malignant disease. A specific CLU immunoreactivity was present in all the endometrial glandular cells in comparison to the other cellular compartments where CLU immunoreactivity was lower or absent. In conclusion, our results suggest the existence of a complex regulatory mechanism of CLU gene expression during the progression from normal to malignant cells, possibly contributing to endometrial carcinogenesis. Moreover, the specific alteration of the sCLU:nCLU ratio associated with the pathological stage, suggests a possible usage of CLU as molecular biomarker for the diagnosis/prognosis of endometrial proliferative diseases.

View Figures

View References

1	Oehler MK, Brand A and Wain GV: Molecular genetics and endometrial cancer. J Br Menopause Soc. 9:27–31. 2003. View Article : Google Scholar : PubMed/NCBI
2	Wunsche W, Tenniswood MP, Schneider MR and Vollmer G: Estrogenic regulation of clusterin mRNA in normal and malignant endometrial tissue. Int J Cancer. 76:684–688. 1998. View Article : Google Scholar : PubMed/NCBI
3	Rosenberg ME and Silkensen J: Clusterin: physiologic and pathophysiologic considerations. Int J Biochem Cell Biol. 27:633–645. 1995. View Article : Google Scholar : PubMed/NCBI
4	Shannan B, Seifert M, Leskov K, Willis J, Boothman D, Tilgen W and Reichrath J: Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer. Cell Death Differ. 13:12–19. 2006. View Article : Google Scholar : PubMed/NCBI
5	Trougakos IP, Lourda M, Agiostratidou G, Kletsas D and Gonos ES: Differential effects of clusterin/apolipoprotein J on cellular growth and survival. Free Radic Biol Med. 38:436–449. 2005. View Article : Google Scholar : PubMed/NCBI
6	Scaltriti M, Santamaria A, Paciucci R and Bettuzzi S: Intracellular clusterin induces G2-M phase arrest and cell death in PC-3 prostate cancer cells. Cancer Res. 64:6174–6182. 2004. View Article : Google Scholar : PubMed/NCBI
7	Scaltriti M, Bettuzzi S, Sharrard RM, Caporali A, Caccamo AE and Maitland NJ: Clusterin overexpression in both malignant and nonmalignant prostate epithelial cells induces cell cycle arrest and apoptosis. Br J Cancer. 91:1842–1850. 2004. View Article : Google Scholar : PubMed/NCBI
8	Andersen CL, Schepeler T, Thorsen K, et al: Clusterin expression in normal mucosa and colorectal cancer. Mol Cell Proteomics. 6:1039–1048. 2007. View Article : Google Scholar : PubMed/NCBI
9	Redondo M, Villar E, Torres-Munoz J, Tellez T, Morell M and Petito CK: Overexpression of clusterin in human breast carcinoma. Am J Pathol. 157:393–399. 2000. View Article : Google Scholar : PubMed/NCBI
10	Kurahashi T, Muramaki M, Yamanaka K, Hara I and Miyake H: Expression of the secreted form of clusterin protein in renal cell carcinoma as a predictor of disease extension. BJU Int. 96:895–899. 2005. View Article : Google Scholar : PubMed/NCBI
11	Pucci S, Bonanno E, Pichiorri F, Angeloni C and Spagnoli LG: Modulation of different clusterin isoforms in human colon tumorigenesis. Oncogene. 23:2298–2304. 2004. View Article : Google Scholar : PubMed/NCBI
12	July LV, Beraldi E, So A, Fazli L, Evans K, English JC and Gleave ME: Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther. 3:223–232. 2004.PubMed/NCBI
13	Scaltriti M, Brausi M, Amorosi A, et al: Clusterin (SGP-2, ApoJ) expression is downregulated in low- and high-grade human prostate cancer. Int J Cancer. 108:23–30. 2004. View Article : Google Scholar : PubMed/NCBI
14	Hassan MK, Watari H, Han Y, et al: Clusterin is a potential molecular predictor for ovarian cancer patient’s survival: targeting Clusterin improves response to paclitaxel. J Exp Clin Cancer Res. 113:1–14. 2011.PubMed/NCBI
15	Watari H, Ohta Y, Hassan MK, Xiong Y, Tanaka S and Sakuragi N: Clusterin expression predicts survival of invasive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy. Gynecol Oncol. 108:527–532. 2008. View Article : Google Scholar
16	Wellmann A, Thieblemont C, Pittaluga S, Sakai A, Jaffe ES, Siebert P and Raffeld M: Detection of differentially expressed genes in lymphomas using cDNA arrays: identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas. Blood. 96:398–404. 2000.PubMed/NCBI
17	Moretti RM, Marelli MM, Mai S, Cariboni A, Scaltriti M, Bettuzzi S and Limonta P: Clusterin isoforms differentially affect growth and motility of prostate cells: possible implications in prostate tumorigenesis. Cancer Res. 67:10325–10333. 2007. View Article : Google Scholar : PubMed/NCBI
18	Gleave M and Chi KN: Knock-down of the cytoprotective gene, clusterin, to enhance hormone and chemosensitivity in prostate and other cancers. Ann NY Acad Sci. 1058:1–15. 2005. View Article : Google Scholar : PubMed/NCBI
19	Seol MB, Bong JJ and Baik M: Expression profiles of apoptosis genes in mammary epithelial cells. Mol Cells. 20:97–104. 2005.PubMed/NCBI
20	Miyake H, Hara I, Fujisawa M and Gleave ME: The potential of clusterin inhibiting antisense oligodeoxynucleotide therapy for prostate cancer. Expert Opin Investig Drugs. 15:507–517. 2006. View Article : Google Scholar : PubMed/NCBI
21	Ahn HJ, Bae J, Lee S, Ko JE, Yoon S, Kim SJ and Sakuragi N: Differential expression of clusterin according to histological type of endometrial carcinoma. Gynecol Oncol. 110:222–229. 2008. View Article : Google Scholar : PubMed/NCBI
22	Perlino E, Lovecchio M, Vacca RA, et al: Regulation of mRNA and protein levels of beta1 integrin variants in human prostate carcinoma. Am J Pathol. 157:1727–1734. 2000. View Article : Google Scholar : PubMed/NCBI
23	Moro L, Greco M, Ditonno P, Battaglia M, Marra E and Perlino E: Transcriptional regulation of the β1C integrin splice variant in human prostate adenocarcinoma. Int J Oncol. 23:1601–1606. 2003.
24	Perlino E, Tommasi S, Moro L, Bellizzi A, Marra E, Casavola V and Reshkin SJ: TGF-β1 and IGF-1 expression are differently regulated by serum in metastatic and non-metastatic human breast cancer cells. Int J Oncol. 16:155–160. 2000.
25	Maiorano E, Ciampolillo A, Viale G, et al: Insulin-like growth factor 1 expression in thyroid tumors. Appl Immunohistochem Mol Morphol. 8:110–119. 2000. View Article : Google Scholar : PubMed/NCBI
26	Perlino E, Moro L, Loverro G, Maiorano E, Selvaggi L and Marra E: Role of the growth factors IGF-1 and TGF-beta 1 in the endometrial adenocarcinoma. Int J Med Biol Env. 29:193–200. 2001.
27	Vacca RA, Marra E, Loverro G, et al: Differential expression of beta 1c integrin messenger ribonucleic acid and protein levels in human endometrium and decidua during the menstrual cycle and pregnancy. J Clin Endocrinol Metab. 88:720–729. 2003. View Article : Google Scholar
28	Lovecchio M, Maiorano E, Vacca RA, et al: Beta 1C integrin expression in human endometrial proliferative diseases. Am J Pathol. 163:2543–2553. 2003. View Article : Google Scholar : PubMed/NCBI
29	Tommasi S, Fedele V, Lacalamita R, Crapolicchio A, Perlino E, Bellizzi A and Paradiso A: Molecular and functional characteristics of erbB2 in normal and cancer breast cells. Cancer Lett. 209:215–222. 2004. View Article : Google Scholar : PubMed/NCBI
30	Vacca RA, Moro L, Maiorano E, Selvaggi L, Marra E and Perlino E: Alternatively spliced variants of b1 integrin are involved in the modulation of human endometrial transformation in different physiological/pathological conditions. Recent Res Devel Proteins. 2:25–47. 2004.
31	Ciampolillo A, De Tullio C, Perlino E and Maiorano E: The IGF-I axis in thyroid carcinoma. Curr Pharm Des. 13:729–735. 2007. View Article : Google Scholar : PubMed/NCBI
32	Moro L, Perlino E, Marra E, Languino LR and Greco M: Regulation of beta1C and beta1A integrin expression in prostate carcinoma cells. J Biol Chem. 279:1692–1702. 2004. View Article : Google Scholar : PubMed/NCBI
33	Moro L, Greco M, Maiorano E, Selvaggi L, Marra E and Perlino E: Transcriptional regulation of β1 integrin expression in the physio/pathological states of human endometrial tissues. Int J Oncol. 26:457–465. 2005.
34	Fuzio P, Lucarelli G, Perlino E, Battaglia M, Bettocchi C, Selvaggi FP and Ditonno P: Androgen deprivation therapy regulation of β1C integrin expression in prostate cancer. Oncol Rep. 22:327–335. 2009.
35	Fuzio P, Ditonno P, Lucarelli G, Battaglia M, Trabucco S and Perlino E: Androgen deprivation therapy affects BCL-2 expression in human prostate cancer. Int J Oncol. 39:1233–1242. 2011.PubMed/NCBI
36	Fuzio P, Ditonno P, Rutigliano M, et al: Regulation of TGF-β1 expression by androgen deprivation therapy of prostate cancer. Cancer Lett. 318:135–144. 2012.
37	Benedet JL, Bender H, Jones H, Ngan HY and Pecorelli S: FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 70:209–262. 2000. View Article : Google Scholar : PubMed/NCBI
38	Bhatia P, Taylor WR, Greenberg AH and Wright JA: Comparison of glyceraldehyde-3-phosphate dehydrogenase and 28S-ribosomal RNA gene expression as RNA loading controls for northern blot analysis of cell lines of varying malignant potential. Anal Biochem. 216:223–226. 1994. View Article : Google Scholar
39	Peirson SN, Butler JN and Foster RG: Experimental validation of novel and conventional approaches to quantitative real-time PCR data analysis. Nucleic Acids Res. 31:e732003. View Article : Google Scholar : PubMed/NCBI
40	Rizzi F and Bettuzzi F: The clusterin paradigm in prostate and breast carcinogenesis. Endocr Relat Cancer. 17:R1–R17. 2010. View Article : Google Scholar : PubMed/NCBI
41	Nieminen TT, Gylling A, Abdel-Rahman WM, et al: Molecular analysis of endometrial tumorigenesis: importance of complex hyperplasia regardless of atypia. Clin Cancer Res. 15:5772–5783. 2009. View Article : Google Scholar : PubMed/NCBI
42	Castrignanò T, D’Antonio M, Anselmo A, et al: ASPicDB: a database resource for alternative splicing analysis. Bioinformatics. 24:1300–1304. 2008.
43	Martelli PL, D’Antonio M, Bonizzoni P, et al: ASPicDB: a database of annotated transcript and protein variants generated by alternative splicing. Nucleic Acids Res. 39:D80–D85. 2011. View Article : Google Scholar : PubMed/NCBI
44	Riva A and Pesole G: A unique, consistent identifier for alternatively spliced transcript variants. PLoS One. 4:e76312009. View Article : Google Scholar : PubMed/NCBI
45	Xie D, Lau SH, Sham JS, et al: Up-regulated expression of cytoplasmic clusterin in human ovarian carcinoma. Cancer. 103:277–283. 2005. View Article : Google Scholar : PubMed/NCBI
46	Brown TL, Moulton BC, Baker VV, Mira J and Harmony JA: Expression of apolipoprotein J in the uterus is associated with tissue remodeling. Biol Reprod. 52:1038–1049. 1995. View Article : Google Scholar : PubMed/NCBI
47	Bettuzzi S, Scorcioni F, Astancolle S, Davalli P, Scaltriti M and Corti A: Clusterin (SGP-2) transient overexpression decreases proliferation rate of SV40-immortalized human prostate epithelial cells by slowing down cell cycle progression. Oncogene. 21:4328–4334. 2002. View Article : Google Scholar
48	Bettuzzi S, Astancolle S, Guidetti G, Moretti M, Tiozzo R and Corti A: Clusterin (SGP-2) gene expression is cell cycle dependent in normal human dermal fibroblasts. FEBS Lett. 448:297–300. 1999. View Article : Google Scholar : PubMed/NCBI
49	Goldberg GS, Jin Z, Ichikawa H, Naito A, Ohki M, El-Deiry WS and Tsuda H: Global effects of anchorage on gene expression during mammary carcinoma cell growth reveal role of tumor necrosis factor-related apoptosis-inducing ligand in anoikis. Cancer Res. 61:1334–1337. 2001.
50	Caccamo AE, Desenzani S, Belloni L, Borghetti AF and Bettuzzi S: Nuclear clusterin accumulation during heat shock response: implications for cell survival and thermotolerance induction in immortalized and prostate cancer cells. J Cell Physiol. 207:208–219. 2006. View Article : Google Scholar
51	Frisch SM and Screaton RA: Anoikis mechanisms. Curr Opin Cell Biol. 13:555–562. 2001. View Article : Google Scholar : PubMed/NCBI
52	Trougakos IP, Djeu JY, Gonos ES and Boothman DA: Advances and challenges in basic and translational research on clusterin. Cancer Res. 69:403–406. 2009. View Article : Google Scholar : PubMed/NCBI
53	Yang CR, Leskov K, Hosley-Eberlein K, Criswell T, Pink JJ, Kinsella TJ and Boothman DA: Nuclear clusterin/XIP8, an x-ray-induced Ku70-binding protein that signals cell death. Proc Natl Acad Sci USA. 97:5907–5912. 2000. View Article : Google Scholar : PubMed/NCBI
54	Petropoulou C, Trougakos IP, Kolettas E, Toussaint O and Gonos ES: Clusterin/apolipoprotein J is a novel biomarker of cellular senescence that does not affect the proliferative capacity of human diploid fibroblasto. FEBS Lett. 509:287–297. 2001. View Article : Google Scholar
55	Gonos ES, Derventzi A, Kveiborg M, Agiostratidou G, Kassem M, Clark BF, Jat PS and Rattan SI: Cloning and identification of genes that associate with mammalian replicative senescence. Exp Cell Res. 240:66–74. 1998. View Article : Google Scholar : PubMed/NCBI
56	Miyake H, Hara I, Kamidono S, Gleave ME and Eto H: Resistance to cytotoxic chemotherapy-induced apoptosis in human prostate cancer cells is associated with intracellular clusterin expression. Oncol Rep. 10:469–473. 2003.
57	Miyake H, Hara I, Gleave ME and Eto H: Protection of androgen-dependent human prostate cancer cells from oxidative stress-induced DNA damage by overexpression of clusterin and its modulation by androgen. Prostate. 61:318–323. 2004. View Article : Google Scholar : PubMed/NCBI
58	Zellweger T, Kiyama S, Chi K, Miyake H, Adomat H, Skov K and Gleave ME: Overexpression of the cytoprotective protein clusterin decreases radiosensitivity in the human LNCaP prostate tumour model. BJU Int. 92:463–469. 2003. View Article : Google Scholar : PubMed/NCBI