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Expression and prognostic value of LRIG1 and the EGF-receptor family in renal cell and prostate cancer
Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The epidermal growth factor receptor (EGFR) family consists of four (EGFR, ErbB2, Erbb3, and ErbB4) receptor tyrosine kinases (RTK) whose signalling is important for physiological and malignant cellular functions such as proliferation, survival, migration, and differentiation. EGFR and ErbB2 in particular are established oncogenes in many solid tumours and are targets for anti-cancer treatment. LRIG1 (leucine-rich repeats and immunoglobulin-like domains-1) is a protein that negatively regulates the EGFR-family, and other RTKs and is a proposed tumour suppressor. This thesis examines the expression of the EGFR-family members and LRIG1 in renal cell carcinoma (RCC) and in prostate cancer (PC).

In RCC, up-regulation of EGFR was shown for all RCC types analysed: clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC). ErbB2 was down-regulated in ccRCC. ErbB3 expression was low in non-neoplastic kidney and not significantly altered in RCC. ErbB4 was strongly down-regulated in the vast majority of RCCs of all types. LRIG1 was down-regulated in ccRCC. No prognostic value was found for any of these factors in RCC. In prostate cancer cells, LRIG1 was shown to be up-regulated by androgen stimulation and suppressed the growth of prostate cancer cells. In prostate cancer, the expression and prognostic value of LRIG1 was investigated in two patient series, one with untreated patients and one with patients who had undergone prostatectomy. In the untreated patient series, LRIG1 correlated with malignancy grade (Gleason score) and poor outcome for patients (both cancer specific and overall survival), being an independent prognostic factor. In contrast, in the series of patients who had undergone prostatectomy, LRIG1 expression correlated with a good outcome (overall survival).

Thus in RCC, there were alterations in gene-expression of the EGFR-family members and LRIG1 between kidney cortex and RCC and between the RCC types. Despite few associations with clinical factors, these alterations are likely to be of biological importance. In prostate cancer LRIG1 was up-regulated by androgen stimulation and inhibited cell proliferation. LRIG1 expression had prognostic value in prostate cancer, maybe as a secondary marker of androgen receptor activation or because of growth inhibition of prostate cancer cells. Contradicting findings in untreated patients and patients treated with prostatectomy poses the question of whether the prognostic value of LRIG1 and other markers vary depending on the specific biological and clinical circumstances in the materials studied.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2009. , 69 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1289
Keyword [en]
Prostate cancer, Renal cell carcinoma, EGFR, ErbB1-4, LRIG1
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-29865ISBN: 978-91-7264-853-1 (print)OAI: oai:DiVA.org:umu-29865DiVA: diva2:278349
Public defence
2009-12-18, Sal 244 Lionssalen, By 7, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-11-30 Created: 2009-11-25 Last updated: 2010-01-18Bibliographically approved
List of papers
1. LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis
Open this publication in new window or tab >>LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis
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2003 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 89, no 7, 1285-1289 p.Article in journal (Refereed) Published
Abstract [en]

In all, 31 renal cell carcinomas (RCCs) were examined for expression of the potential tumour suppressor LRIG1 (formerly Lig-1) and the epidermal growth factor receptor (EGFR). Eight matched samples of uninvolved kidney cortex were also evaluated. Gene expression was examined by quantitative real-time RT-PCR. In the eight matched sample pairs (uninvolved kidney cortex and tumour), protein expression was examined by immunohistochemistry. Conventional (clear cell) tumours showed an expected upregulation of EGFR. LRIG1 expression was generally downregulated in conventional and papillary RCC but not in chromophobic RCC. The ratio between EGFR and LRIG1 was more than 2.5-fold higher in the eight tumours compared with matched uninvolved kidney cortex and was at least two-fold higher than the mean normal ratio in 21 of 31 samples analysed. The observed downregulation of LRIG1 and increased EGFR/LRIG1 ratios are consistent with LRIG1 being a suppressor of oncogenesis in RCC by counteracting the tumour-promoting properties of EGFR. Further studies are justified to elucidate the explicit role of LRIG1 in the oncogenesis of RCC.

Identifiers
urn:nbn:se:umu:diva-29777 (URN)10.1038/sj.bjc.6601208 (DOI)14520461 (PubMedID)
Available from: 2009-11-25 Created: 2009-11-23 Last updated: 2017-12-12Bibliographically approved
2. ErbB4 is downregulated in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis of the epidermal growth factor receptor family
Open this publication in new window or tab >>ErbB4 is downregulated in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis of the epidermal growth factor receptor family
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2004 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 43, no 5, 453-459 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-15596 (URN)10.1080/02841860410028574 (DOI)15360049 (PubMedID)
Available from: 2007-05-24 Created: 2007-05-24 Last updated: 2017-12-14Bibliographically approved
3. Differences and similarities in the expression of the epidermal growth factor receptor family and the proposed tumor suppressor LRIG1 in types of renal cell carcinoma as analyzed by quantitative real-time RT-PCR
Open this publication in new window or tab >>Differences and similarities in the expression of the epidermal growth factor receptor family and the proposed tumor suppressor LRIG1 in types of renal cell carcinoma as analyzed by quantitative real-time RT-PCR
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-29778 (URN)
Available from: 2009-11-23 Created: 2009-11-23 Last updated: 2009-11-30Bibliographically approved
4. LRIG1 and the liar paradox in prostate cancer: a study of the expression and clinical significance of LRIG1 in prostate cancer
Open this publication in new window or tab >>LRIG1 and the liar paradox in prostate cancer: a study of the expression and clinical significance of LRIG1 in prostate cancer
Show others...
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-29779 (URN)
Available from: 2009-11-23 Created: 2009-11-23 Last updated: 2009-11-30Bibliographically approved

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