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Expression of PRL proteins at invasive margin of rectal cancers in relation to preoperative radiotherapy
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
2006 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 65, no 2, 452-458 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: PRL-3 (phosphatase of regenerating liver) is involved in metastasis of colorectal cancer; however, its therapeutic implication in cancer patients has not been studied. We investigated the relationships of PRL expression to radiotherapy (RT) in rectal cancer patients.

Methods and Materials: Phosphatase of regenerating liver expression was immunohistochemically examined in distant (n = 36) and adjacent (n = 82) normal mucosa, primary tumor (n = 125), biopsy specimens (n = 96), and lymph node metastasis (n = 30) from rectal cancer patients participating in a clinical trial of preoperative RT.

Results: Phosphatase of regenerating liver expression was increased from the distant to adjacent mucosa and to the primary tumor (p < 0.05). PRL was highly expressed at the invasive margin in 28% of the primary tumors and 26% of the metastases. In the RT group, strong PRL expression at the invasive margin was related to distant recurrence (p = 0.006) and poor survival (p = 0.01), but not in the non-RT group. The survival significance remained even after adjusting for Dukes’ stage and differentiation (p = 0.02). Additional multivariate analyses showed that the correlation with prognostic significance of PRL differed between the RT and non-RT groups (p = 0.01).

Conclusion: Phosphatase of regenerating liver expression (rather than PRL-3 alone) at the invasive margin predicted resistance to RT and unfavorable survival in rectal cancer patients with preoperative RT.

Place, publisher, year, edition, pages
2006. Vol. 65, no 2, 452-458 p.
Keyword [en]
Phosphatase of regenerating liver; PRL; Invasive margin; Radiotherapy; Prognosis; Rectal cancer
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-14784DOI: 10.1016/j.ijrobp.2005.12.043PubMedID: 16626893OAI: oai:DiVA.org:liu-14784DiVA: diva2:25262
Available from: 2008-09-24 Created: 2008-09-24 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Molecular Studies of Irradiation and SN-38 on Colorectal Cancer
Open this publication in new window or tab >>Molecular Studies of Irradiation and SN-38 on Colorectal Cancer
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer (CRC) is one of most common cancer diseases worldwide. In Swedenapproximately 5,000 new cases of CRC are generated each year, which makes it the thirdmost common cancer disease among both men and women. The past decades ofimproved treatment strategies have considerably increased the five-year survival for CRCpatients. However more could be achieved in this area, in particular for metastatic CRC,which is the cause of most CRC-related deaths. Therefore it is important to study thebiological response to certain treatments induced in CRC to find valuable predictiveand/or prognostic factors to select patients for better suited treatments.

The aim of this thesis was to gain insight into the molecular changes that occurfollowing irradiation or treatment with SN-38 in rectal cancer patients or colon cancercell lines by studying the RNA expression, protein expression, DNA cell cycledistribution and apoptotic response. The expression of phosphatase of regenerating liver(PRL) proteins was investigated in rectal cancers from 125 patients included in arandomized clinical trial of preoperative radiotherapy (RT). Increased expression of PRLswas seen at the invasive margin of primary and metastatic cancers compared with theinner area of the tumors. Moreover, strong PRL staining at the invasive margin correlatedto distant recurrence and worse survival of patients in the RT group but not in non-RTgroup (Paper I). Radiosensitivity was studied by treating KM12C, KM12SM andKM12L4a colon cancer cell lines with radiation. KM12C is of low metastatic naturecompared with the highly metastatic KM12SM and KM12L4a. Upregulation of ΔNp73and PRL-3 might contribute to the radioresistant phenotype in KM12C. In contrast,KM12L4a shows a high frequency of apoptosis and lack of upregulation of ΔNp73, PRL-3 and survivin, which might explain its radiosensitive phenotype (Paper II). KM12C,KM12SM and KM12L4a were treated with SN-38 which inhibits topoisomerase 1 (topo-1). The results show that SN-38 induces G2/S arrest and possess the capacity to triggerapoptosis in the three cell lines (Paper III). To further elucidate SN-38 effect on these celllines, the gene expression profile following SN-38 treatment was studied. Oligonucleotidearrays consisting of ~27,000 spots were hybridized with sample and reference cDNA.Both unsupervised and supervised hierarchical clustering analysis, and functional analysiswere performed. Supervised hierarchical clustering gives a strong signal of 1453discriminated genes, the vast majority being upregulated. Both upregulated anddownregulated genes point toward a favorable impact of SN-38 regarding the apoptoticpathways. For example RhoB and Bax are upregulated together with downregulation ofKras and survivin, which promotes apoptosis (Paper IV).

In conclusion, PRLs may be valuable biomarkers for RT resistance, predicting apoor prognosis in rectal cancer patients. Targeting radio-resistance factors, such asΔNp73 and survivin may contribute to an increased sensitivity to RT. SN-38 affects cellproliferation and apoptosis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. 60 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1070
Keyword
Colorectal cancer (CRC), molecular changes, SN-38
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-14789 (URN)978-91-7393-838-9 (ISBN)
Public defence
2008-09-29, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
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Supervisors
Available from: 2008-09-24 Created: 2008-09-24 Last updated: 2009-08-22Bibliographically approved

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Wallin, Åsa R.Svanvik, JoarAdell, GunnarSun, Xiao-Feng

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