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RAD50/MRE11/NBS1 proteins in relation to tumour development and prognosis in patients with microsatellite stable colorectal cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
Division of Biomedicine, School of Life Science, Skövde University, Skövde, Sweden.
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.
2008 (English)In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 23, 1495-1502 p.Article in journal (Refereed) Published
Abstract [en]

RAD50/MRE11/NBS1 complex is essential for DNA double-strand break repair and for maintaining genomic integrity. In this study, we immunohisto-chemically examined MRE11, NBS1 and RAD50 expression in primary CRCs (n=208), the corresponding distant (n=41) and adjacent normal mucosa (n=130), and lymph node metastases (n=26), and investigated their clinicopathological significance in colorectal cancers (CRCs). We found that the intensity and percentage of MRE11 and NBS1 in primary CRCs were positively correlated with each other and with RAD50 (P<0.0001). Strong expression of MRE11, NBS1 or combined RAD50/MRE11/NBS1 was related to MSS, positive hMLH1 expression, earlier tumour stage (TNM stage I and II) and favourable survival (P<0.05). A high percentage of MRE11 expression was associated with less local recurrence and high apoptotic activity (P<0.05). In MSS CRCs, the expression of MRE11 and NBS1 was stronger than that in normal mucosa (P<0.05), and strong expression of NBS1 in primary tumour was related to favourable survival of patients in TNM stage I and II (univariate analysis: P=0.03; multivariate analysis: P=0.07). In MSI CRCs, neither MRE11 nor NBS1 expression showed differences among normal mucosa, primary tumour and metastasis, or among clinicopathological variables. In conclusion, RAD50/MRE11/NBS1 proteins interacted with each other, which had different clinicopathlogical significance in MSS and MSI CRCs, and further, each component of the complex might have additional roles. NBS1 might be a prognostic factor for patients with MSS tumour in TNM stage I and II.

Place, publisher, year, edition, pages
2008. Vol. 23, 1495-1502 p.
Keyword [en]
RAD50, MRE11, NBS1, Prognosis, Colorectal cancer
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-12871OAI: oai:DiVA.org:liu-12871DiVA: diva2:17252
Available from: 2008-01-07 Created: 2008-01-07 Last updated: 2017-12-14
In thesis
1. Molecular and Biological Characteristics of Stroma and Tumor Cells in Colorectal Cancer
Open this publication in new window or tab >>Molecular and Biological Characteristics of Stroma and Tumor Cells in Colorectal Cancer
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Carcinogenesis is a progressive process involving multiple genetic alterations in tumor cells and complex interactions in the tumor-host microenvironment. To better understand the contribution of molecular alterations in tumor cells and stromal variables to the development of colorectal cancer (CRC) and identify prognostic factors, in this study we examined the clinicopathological and biological significance of stromal variables, including particularly interesting new cysteine-histidine rich protein (PINCH), inflammatory infiltration, angiogenesis and lymphangiogenesis, as well as hRAD50/hMRE11/hNBS1 proteins and hRAD50 mutation in tumor cell in CRC.

PINCH protein expression in the stroma was increased from normal mucosa to primary tumors and further to lymph node metastases. In particular, PINCH expression was most intense at the tumor invasive margin, which was related to low inflammatory infiltration and independently related to an unfavorable prognosis. Low inflammatory infiltration at the tumor invasive margin was related to advanced tumor stage, worse differentiation and microsatellite instability (MSI). Further, it was independently related to an unfavorable prognosis. Increased blood and lymphatic vessel density was observed in the primary tumors compared with the corresponding normal mucosa. However, neither angiogenesis nor lymphangiogenesis was associated with tumor stage and patients’ survival. Moreover, PINCH was present in a proportion of endothelial cells of the tumor vasculature, and PINCH expression in tumor-associated stroma was positively related to blood vessel density.

In primary tumor cells of CRC, strong expression of hRAD50, hMRE11 or hNBS1 was related to microsatellite stability (MSS). A high percentage of hMRE11 expression was associated with less local recurrence and high apoptotic activity. Further, we observed that the expression of hRAD50, hMRE11 or hNBS1 among normal mucosa, primary tumors and metastases in MSS CRC differed from that in MSI CRC. In MSS CRC, the expression intensity of hRAD50, hMRE11 and hNBS1 was consistently increased with respect to normal mucosa, but there was no difference between the primary tumors and metastases. In the primary MSS tumors, the expression of individual or combination of hRAD50/hMRE11/hNBS1 was associated with a favorable prognosis in the same series of the CRCs. Moreover, strong/high hRAD50 in MSS primary tumors was related to earlier tumor stage, better differentiation and high inflammatory infiltration, whereas strong hNBS1 expression tended to be independently related to a favorable prognosis in MSS CRC with earlier tumor stage. However, in MSI CRC, there were neither differences in the expression of hRAD50/hMRE11/hNBS1 among normal mucosa, primary tumors and metastases, nor any association of the protein expressions with clinicopathological variables. On the other hand, frameshift mutations of (A)9 at coding region of hRAD50 were only found in MSI CRC.

Our study indicates that 1) PINCH is likely a regulator of angiogenesis, and PINCH expression at the tumor invasive margin is an independent prognostic indicator in CRC. 2) Inflammatory infiltration at the tumor invasive margin is also an independent prognostic indicator in CRC. The lack of association between high inflammatory infiltration and MSI may help to explain the non-association of MSI with survival in CRC patients. 3) Angiogenesis and lymphangiogenesis occur in the early stage of CRC development, but do not associate with CRC progression and patients’ prognosis. 4) hRAD50/hMRE11/hNBS1 may act dependently and independently, playing different roles in MSS and MSI CRC development. In MSS CRC, the strong expression of the three proteins, associated with a favorable prognosis, may present the cellular response against tumor progression. Expression of hNBS1 may be a prognostic indicator for MSS CRC patients in the earlier tumor stage. In MSI CRC, the frameshift mutations at the coding region of hRAD50 may contribute to tumor development.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2008
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1029
Keyword
Carcinogenesis, genetic alterations, colorectal cancer (CRC), cysteine-histidine rich protein (PINCH), Inflammatory infiltration, Angiogenesis, lymphangiogenesis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-10516 (URN)978-91-85895-51-9 (ISBN)
Public defence
2008-01-25, Eken, Campus US, Linköpings universitet, Linköping, 13:00 (English)
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Supervisors
Available from: 2008-01-07 Created: 2008-01-07 Last updated: 2015-11-19

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Gao, JingfangZhang, HongArbman, GunnarSun, Xiao-Feng

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