Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The clinical and prognostic correlation of HRNPM and SLC1A5 in pathogenesis and prognosis in epithelial ovarian cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Reproduktiv hälsa)
Department of Pathology, Halmstad Medical Center Hospital, Halmstad, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Reproduktiv hälsa/Sundström Poromaa)ORCID iD: 0000-0002-2491-2042
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Show others and affiliations
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0179363Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To evaluate the prognostic effect of the Heterogeneous nuclear ribonucleoprotein type M (HNRPM) and Solute carrier 1A5 (SLC1A5) in FIGO-stages I-II epithelial ovarian cancer.

METHODS: A retrospective cohort study was designed to investigate the prognostic effect of HNRPM and SLC1A5, and the association with clinical-pathologic characteristics in 131 patients with FIGO-stages I-II epithelial ovarian cancer. Tissue microarrays were constructed and protein levels were assessed by immunohistochemistry (IHC).

RESULTS: Positive HRNPM status was associated with positive staining for PUMA (P = 0.04), concomitant PUMA and p21 staining (P = 0.005), and VEGF-R2 (P = 0.003). Positive SLC1A5 staining was associated with positive staining of p27 (P = 0.030), PUMA (P = 0.039), concomitant PUMA and p27 staining, and VEGF-R2 (P = 0.039). In non-serous tumors (n = 72), the SLC1A5 positivity was associated with recurrent disease (P = 0.01). In a multivariable logistic regression analysis FIGO-stage (OR = 12.4), tumor grade (OR = 5.1) and SLC1A5 positivity (OR = 0.1) were independent predictive factors for recurrent disease. Disease-free survival (DFS) in women with SLC1A5-positive non-serous tumors was 92% compared with of 66% in patients with SLC1A5-negative non-serous tumors (Log-rank = 15.343; P = 0.008). In Cox analysis with DFS as endpoint, FIGO-stage (HR = 4.5) and SLC1A5 status (HR = 0.3) were prognostic factors.

CONCLUSIONS: As the proteins HRNPM and SLC1A5 are associated with the cell cycle regulators p21 or p27, the apoptosis regulators PTEN and PUMA, and the VEGF-R2 it is concluded that both proteins have role in the pathogenesis of ovarian cancer. In patients with non-serous ovarian cancer SLC1A5 protects from recurrent disease, presumably by means of biological mechanisms that are unrelated to cytotoxic drug sensitivity.

Place, publisher, year, edition, pages
2017. Vol. 12, no 6, article id e0179363
National Category
Obstetrics, Gynecology and Reproductive Medicine Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-327289DOI: 10.1371/journal.pone.0179363ISI: 000403274700031PubMedID: 28609484OAI: oai:DiVA.org:uu-327289DiVA, id: diva2:1130164
Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2018-04-23Bibliographically approved
In thesis
1. Predictive and prognostic factors of epithelial ovarian cancer and pseudomyxoma peritonei
Open this publication in new window or tab >>Predictive and prognostic factors of epithelial ovarian cancer and pseudomyxoma peritonei
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The overall aim of my thesis was to investigate potential prognostic and predictive factors associated with the tumor cells of epithelial ovarian cancer (EOC) and the gastrointestinal tumor pseudomyxoma peritonei (PMP) to improve and individualize cancer therapy. Both PMP and EOC can develop into peritoneal carcinomatosis (PC), which is characterized by widespread metastasis of cancer tumors in the peritoneal cavity. Major improvements in the management of PC, such as cytoreductive surgery in combination with chemotherapy, have dramatically changed the prognosis.

To further optimize and tailor treatment, increased knowledge on tumor biology and pathogenesis is needed. Today’s choice of treatment is mainly based on clinical trials and standard protocols that have not taken individual differences in drug sensitivity into consideration. With ex vivo testing of tumor drug sensitivity, individuals at risk of side effects only (and no treatment benefit) could potentially be identified prior to treatment.

Napsin A is an anti-apoptotic protein that promotes platinum resistance by degradation of the cell cycle regulator and tumor suppressor TP53. Immunohistochemical stainings of 131 early EOC tumors in study I showed that expression of Napsin A was associated with expression of the apoptosis regulators p21 and p53 and with histological subtype. Positivity of Napsin A in an epithelial ovarian tumor strengthens the morphological diagnosis of clear cell carcinoma and should be useful in diagnostics. In study II, the relevance of the proteins HRNPM and SLC1A5 as prognostic factors for recurrent disease, survival and impact on clinical or pathological features was evaluated in 123 patients with early EOC. Our results support concomitant positivity of HRMPM and PUMA/p21 in ovarian cancer and indicate that HRNPM may trigger activity in systems of cell cycle regulation and apoptosis. In subgroup analyses of tumors from patients with non-serous EOC histology, expression of SLC1A5 was shown to be a prognostic factor in terms of prolonged disease-free survival. In studies III and VI, we investigated the ex vivo drug sensitivity of tumor cells from EOC and PMP with the 72-h cell viability assay fluorometric microculture cytotoxicity assay (FMCA). The two studies confirm that drug sensitivity varies considerably between tumor samples from patients within the same diagnostic group. In ovarian cancer, ex vivo results show that type I tumors were generally less sensitive to cytotoxic agents than type II tumors. Samples from patients previously exposed to cytotoxic drugs generally tended to be more resistant to most drugs than samples from unexposed patients in both EOC and PMP. This observation is in line with clinical experience and findings supporting that exposure to cytotoxic treatments contribute to development of chemo-resistance mechanisms. In ovarian cancer, resistance to the kinase inhibitors after exposure varied but was less pronounced than that for standard cytotoxic drugs. In PMP patients, ex vivo drug sensitivity provided prognostic information for progression-free survival, and this is in line with earlier findings.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 65
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1462
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-349159 (URN)978-91-513-0326-0 (ISBN)
Public defence
2018-06-08, Gustavianum, auditorium minus, Akademigatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2018-05-17 Created: 2018-04-22 Last updated: 2018-05-17

Open Access in DiVA

fulltext(4582 kB)20 downloads
File information
File name FULLTEXT01.pdfFile size 4582 kBChecksum SHA-512
76412a32f536f4b13dceaf2556187daef6642b4ca973a37ef943fc99d1e31c71f21aa1982b5805b752c95dfeb2842f3a8e887e0ae9b68d3c5c45c189c12793cf
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Bjersand, KathrineSundström Poromaa, IngerÅkerud, HelenaSkírnisdottir, Ingiridur
By organisation
Obstetrics and GynaecologyMedicinsk genetik och genomik
In the same journal
PLoS ONE
Obstetrics, Gynecology and Reproductive MedicineCancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar
Total: 20 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 259 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf