Lead article
Changes in gene expression during progression of ovarian carcinoma

https://doi.org/10.1016/S0165-4608(01)00386-7Get rights and content

Abstract

The molecular events leading to the development and progression of serous ovarian carcinoma are not completely understood. We performed a large scale survey for the identification of differentially expressed genes in serous ovarian carcinoma by using cDNA array analysis. Differences in gene expression between serous adenocarcinoma and benign serous adenoma, and between advanced and/or moderately or poorly differentiated and local, highly differentiated serous adenocarcinoma were assessed. The most striking difference between adenocarcinoma and benign adenoma was upregulation of RHOGDI2 in the carcinomas irrespective of the clinical tumor stage. Other changes in carcinoma were upregulation of MET and Ne-dlg, and downregulation of HGFAC, desmin, and PDGFA. The most prominent differences between advanced and local adenocarcinoma were upregulation of COL3A1, CFGR, and MET in advanced carcinoma, and downregulation of HGFAC, FZD3, and BFL1 in the same tumors. In conclusion, significant differences were found in the gene expression between benign and malignant serous ovarian tumors, and between local, highly differentiated and advanced and/or moderately or poorly differentiated serous adenocarcinomas. The differentially expressed genes may be related to the carcinogenesis and progression of the malignant growth.

Introduction

The majority of ovarian malignancies arise from the surface epithelium. They are classified into several histological subtypes according to their cell type, serous, mucinous and endometrioid types being the most common. Tumors with serous histology comprise approximately 50% of the cases. The biological and clinical course of serous ovarian carcinoma is characterized by invasive behaviour, early dissemination to the peritoneal cavity, and poor prognosis [1].

Knowledge of the molecular genetic background of ovarian carcinoma is still scarce. The different histological subtypes of ovarian carcinoma share numerous genetic changes, and some alterations are specific for a certain histological subtype. Serous ovarian carcinoma exhibits frequent abnormal cytogenetic karyotypes, common DNA sequence copy number changes at chromosome 8 2, 3, 4, and molecular genetic changes in the ERBB2 and TP53 genes 5, 6. However, several other yet unidentified genes are most probably involved in the development and progression of serous ovarian carcinoma.

Gene expression studies provide means for finding the genes relevant for cancer development and progression. A new approach is a complementary DNA (cDNA) microarray technique, which allows simultaneous expression analysis of hundreds or even thousands of genes in the sample of interest. This large scale expression survey has been successfully applied to investigate gene expression profiling in different human cancers 7, 8, 9, 10.

We used cDNA array technique to carry out a large scale survey of differentially expressed genes that might be associated with the development and progression of serous ovarian adenoma to local and advanced adenocarcinoma.

Section snippets

Tissue samples

Tissue samples were obtained from seven patients treated at the Department of Obstetrics and Gynecology, Helsinki University Central Hospital (Table 1). The study was approved by the Institutional Review Board. The samples were snap frozen in liquid nitrogen and stored at −70°C before RNA isolation. All ovarian tumors, including benign adenoma, exhibited serous histology (Table 1). The predominance of tumor cells (80–90%) in each carcinoma sample was microscopically verified.

RNA isolation

The frozen tissue

Ovarian adenocarcinoma versus benign adenoma

All six adenocarcinomas were compared with benign adenoma. Altogether 57 differentially expressed genes were detected in adenocarcinoma. Thirty-eight of these genes were upregulated and 19 were downregulated. Sixteen genes were upregulated and nine were downregulated in all carcinoma samples. The upregulated genes included Rho family genes (Ly-GDI, Rho8, Rho dissociation inhibitor 1), oncogenes and tumor suppressor genes (MET, MDM2s, STAT1, RBQ1), cell-cell interaction genes (Ne-dlg, cadherin

Discussion

The cDNA array analysis of serous ovarian carcinoma disclosed many genes with altered expression levels. Of particular interest are those which were differentially expressed in the majority of tumors, because frequent association may indicate a specific role in the development and progression of serous ovarian carcinoma. Some of the changes found in this study, e.g., overexpression of MET, AKT2 and PCNA 11, 12, 13, have been reported earlier in serous ovarian carcinoma. The present results thus

Acknowledgments

We thank Drs. P. Lehtovirta, A. Tenhunen and K. Ylinen for assistance in collecting the material. The technical assistance of Ms. A. Harju and Ms. R. Soitinaho are gratefully acknowledged. The study was supported by grants from the Helsinki University Hospital Research Funds, the Finnish Cancer Foundation, Finnish Medical Society, Finnish Cultural Foundation, and the Finnish Foundation for Obstetrics and Gynecology.

References (24)

  • A. Berchuk et al.

    Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer

    Cancer Res

    (1990)
  • J.R. Marks et al.

    Overexpression and mutation of p53 in epithelial ovarian cancer

    Cancer Res

    (1991)

    • Cited by (129)

    • Knockdown of RhoGDI2 represses human gastric cancer cell proliferation, invasion and drug resistance via the Rac1/Pak1/LIMK1 pathway

      2020, Cancer Letters
      Citation Excerpt :

      Furthermore, RhoGDI2, which is abundantly expressed in hematopoietic tissues, is selectively downregulated in Hodgkin's lymphoma cells in comparison with non-Hodgkin's lymphoma cells, and the loss of RhoGDI2 expression possibly contributes to the apoptotic resistance of the former cell type [27]. In contrast, the expression of RhoGDI2 is positively correlated with tumour malignancy in ovarian cancer [8]. RhoGDI2 plays a major role in the regulation of breast cancer metastasis and may be a prognostic indicator in patients with invasive ductal breast cancer.

    • PLCγ1: Potential arbitrator of cancer progression

      2018, Advances in Biological Regulation
      Citation Excerpt :

      Rho GDP dissociation inhibitor 2 (RhoGDI2) is often overexpressed in various types of cancer and is closely involved in cancer progression. It augments cancer invasion, metastasis, and resistance to chemotherapeutic agents (Cho et al., 2009, 2011b; Tapper et al., 2001). RhoGDI2 also induces the phosphorylation of PLCγ1.

    • Mapping three-dimensional intratumor proteomic heterogeneity in uterine serous carcinoma by multiregion microsampling

      2024, Clinical Proteomics

    • RhoGDI2 induced malignant phenotypes of pancreatic cancer cells via regulating Snail expression

      2022, Genes and Genomics

    • TGFβ1 induces myofibroblast transdifferentiation via increasing Smad-mediated RhoGDI-RhoGTPase signaling

      2022, General Physiology and Biophysics

    • The Emerging Role of c-Met in Carcinogenesis and Clinical Implications as a Possible Therapeutic Target

      2022, Journal of Oncology
    View all citing articles on Scopus
    View full text
    Copyright © 2001 Elsevier Science Inc. All rights reserved.