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Polymorphism and expression of NF-κB in relation to susceptibility and prognosis of colorectal cancer patients
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Normal human cells are strictly controlled in their environment by extrinsic and intrinsic factors. Despite this, some cells begin to develop into cancer cells, and if this process is allowed to continue, it will develop into cancer disease. To become cancerous, a cell must break several biological barriers. Two important barriers are apoptosis and cellular growth control.

Cancer is a multifactorial disease caused by environmental and hereditary factors. The incidence of colorectal cancer varies among different populations around the world. Sweden has a history of a relatively high incidence of colorectal cancer, whereas its incidence in China is relatively low.

Nuclear factor kappa B (NF-κB) is a transcription factor protein family, regulating genes involved in several aspects of cancer development. In human cells five members have been identified: NFKB1 (p105/p50), NFKB2 (p100/p52), RelA (p65), RelB and c-Rel. They normally form homo- or heterodimers in the cytoplasm of the cells, where they are in an inactive state by binding to inhibitory proteins, I kappaB-α, -θ and -ε and Bcl-3. Stimulatory signals, both intrinsic and extrinsic, lead the inhibitory proteins to be phosphorylated, which marks them for degradation. On activation, NF-κB proteins are often posttranslationally modified.

In the first project, we investigated the role of a polymorphism in the promoter region of NFKB1 gene. The polymorphism is a 4-basepair insertion/deletion located 94 basepairs upstream of the gene (-94ins/delATTG). It does not seem to alter the amino acid sequence of the protein and therefore does not alter the function of the protein itself. Instead, it alters the regulation of the protein transcription. The aim of the present study was to investigate whether the polymorphism was related to cancer risk or clinicopathological variables. We found that this polymorphism increased the risk of sporadic colorectal cancer in a Swedish population but not in Swedish populations with a family history of colorectal cancer or in Chinese population.

In the second project we studied an 8-basepair insertion/deletion polymorphism in the promoter region of NFKBIA gene coding for the nuclear factor kappa B inhibitory protein, IκBα. This polymorphism is located 708 basepairs upstream of the gene (-708ins/del8). The aim of the study was to investigate whether the polymorphism was related to cancer risk or clinicopathological factors. We found that this polymorphism was very rare in a Swedish population of colorectal cancer patients and controls and was totally absent in a Chinese population of patients and controls. Our conclusion is that this polymorphism is too rare to have a major impact on colorectal cancer incidence in the two populations.

In the third project we studied levels of p65 phosphorylated at Serine-536 in colorectal cancers in a Swedish population. After activation and IκB phosphorylation/degradation, p65 is phosphorylated at Serine-536. This phosphorylation is involved in regulating transcriptional activity, nuclear localisation and protein stability. The aim of the study was to investigate whether the expression of the phosphorylated protein correlated to any clinicopathological variables, including survival. The expression of p65 phosphorylated at Serine-536 increased from normal mucosa to primary tumour, but no further increase to lymph node metastases was found. We did find, however, that the strong expression in the cytoplasm was correlated to worse survival among the patients, independent of gender, age, tumour location, stage and differentiation.

In the fourth project we continued to study p65 phosphorylated at Serine-536. In this project, however, we studied the expression in a population of rectal cancer patients who participated in a Swedish clinical trial of preoperative radiotherapy. The aim of the study was to investigate whether the expression correlated to response to radiotherapy or to clinicopathological and some biological factors. We found that the expression was increased from normal mucosa to primary tumour, but detected no further increase from primary tumour to lymph node metastases. We found that the expression of p65 protein phosphorylated at Serine-536 was positively related to expression of TEM1, FXYD-3, PRL, p73 and MAC30 in the group of patients who received radiotherapy. Although no such relationship was seen in the group of patients that had not received radiotherapy, we did not find that the expression of p65 protein phosphorylated at Serine-536 was directly related to the clinical response to radiotherapy.

In summary, the -94ins/delATTG polymorphism in the promoter region of NFKB1 gene increases the risk of sporadic colorectal cancer in Swedish but not in Chinese populations. The -708ins/del8 polymorphism in the promoter region of the NFKBIA gene is too rare to have a major impact on colorectal cancer incidence in Swedish and Chinese populations. Strong expression of p65 protein phosphorylated at Serine-536 is independently related to worse survival in Swedish colorectal cancer patients, and the expression is positively correlated to biological factors associated with more malignant features of tumours in rectal cancer patients who received preoperative radiotherapy.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2010. , 45 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1165
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-53623ISBN: 978-91-7393-452-7 (print)OAI: oai:DiVA.org:liu-53623DiVA: diva2:290289
Public defence
2010-01-29, Eken, Hälsouniversitetet, Campus US, Linköpings univeristet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2010-01-26Bibliographically approved
List of papers
1. Polymorphism in the promoter region of the NFKB1 gene increases the risk of sporadic colorectal cancer in Swedish but not in Chinese populations
Open this publication in new window or tab >>Polymorphism in the promoter region of the NFKB1 gene increases the risk of sporadic colorectal cancer in Swedish but not in Chinese populations
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2007 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 42, no 11, 1332-1338 p.Article in journal (Refereed) Published
Abstract [en]

Objective. An insertion/deletion polymorphism (-94ins/delATTG) in the promoter region of the NFKB1 gene correlates to an increased risk of ulcerative colitis, a known risk factor for colorectal cancer, but this polymorphism has not been studied in colorectal cancer patients. The purpose of this study was to investigate whether this polymorphism is related to colorectal cancer risk and clinicopathological variables. Material and methods. Case samples were taken from four groups of Swedish patients: 193 unselected patients, 90 patients with ≥3 affected 1st-degree relatives, 85 patients with 2 affected 1st-degree relatives, and 109 sporadic cancer patients, and one group of 193 unselected Chinese patients. Controls included 439 Swedish and 458 Chinese healthy individuals. Genotypes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Results. The deletion increased the risk of colorectal cancer among Swedish unselected patients (OR=3.81, 95% CI: 2.17-6.69, p<0.0001 for heterozygote deletion, and OR=4.65, 95% CI: 2.43-8.89, p<0.0001 for homozygote deletion) and sporadic cancer patients (OR=7.73, 95% CI: 3.06-19.57, p<0.0001 for heterozygote deletion, and OR=6.58, 95% CI: 2.35-18.43, p<0.0001 for homozygote deletion) compared to homozygote insertion (wild-type), but not among the other Swedish or Chinese patients (p>0.05). Similar evidence was seen in age-adjusted analyses (p<0.0001). The polymorphism did not correlate to clinicopathological variables (p>0.05). Conclusions. Deletion of the polymorphism was associated with increased susceptibility to sporadic colorectal cancers in the Swedish population, but not in the Swedish patients with a family history of colorectal cancer or in Chinese patients. © 2007 Taylor & Francis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-41614 (URN)10.1080/00365520701396026 (DOI)58353 (Local ID)58353 (Archive number)58353 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
2. Polymorphism in the promoter region of the NFKBIA gene is rare in Swedish and Chinese colorectal cancer patients and controls
Open this publication in new window or tab >>Polymorphism in the promoter region of the NFKBIA gene is rare in Swedish and Chinese colorectal cancer patients and controls
2010 (English)In: MOLECULAR MEDICINE REPORTS, ISSN 1791-2997, Vol. 3, no 1, 69-74 p.Article in journal (Refereed) Published
Abstract [en]

To investigate whether a -708ins/del8 polymorphism in the promoter region of the NFKBIA gene is related to colorectal cancer risk and clinicopathological variables, we, genotyped 92 Swedish and 93 Chinese patients as well as 174 Swedish and 159 Chinese healthy controls by polymerase chain reaction-single stranded conformation polymorphism and DNA sequencing. The -708/del8 polymorphism was found in two Swedish patients and eight Swedish controls, but was absent in the Chinese population. However, among the Chinese population we found other mutations in three patients and in one control. In conclusion, the -708ins/del8 polymorphism is too rare to have a major impact on colorectal cancer incidence in the two populations.

Keyword
NFKBIA; polymorphism; colorectal neoplasm; polymerase chain reaction-single stranded conformation polymorphism; DNA sequencing
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-52887 (URN)10.3892/mmr_00000220 (DOI)
Available from: 2010-01-13 Created: 2010-01-12 Last updated: 2014-10-07
3. NF-κB p65 phosphorylated at Serine-536 is an independent prognostic factor in Swedish colorectal cancer patients
Open this publication in new window or tab >>NF-κB p65 phosphorylated at Serine-536 is an independent prognostic factor in Swedish colorectal cancer patients
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: NF-κB transcription factor protein family has diverse cellular and biological functions, and post-translational modification is important to regulate these functions. An important site of phosphorylation of p65 subunit is at Serine-536 (phospho-Ser536-p65), and this phosphorylation is involved in regulation of transcriptional activity, nuclear localization and protein stability. In this study, we investigated a phospho-Ser536-p65 in colorectal cancers and its relationship to clinicopathological factors of the patients.

Materials and Methods: Expression of phospho-Ser536-p65 was examined by using immunohistochemistry in 203 primary colorectal cancers, 156 normal mucosa specimens and 18 metastases in the lymph nodes.

Results: The expression of phospho-Ser536-p65 increased from normal mucosa to primary tumour (p<0.0001). Further, the increased expression of phospho-Ser536-p65 in the cytoplasm of the primary tumours correlated with worse survival of the patients independent of gender, age, tumor location, stage and differentiation (p=0.04, hazard ratio 1.89, 95% CI 1.03-3.47).

Conclusion: The NF-κB p65 subunit phosphorylated at Serine-536 is anindependent prognostic factor in colorectal cancer patients.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53621 (URN)
Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2010-01-26
4. Expression of NF-κB p65 phosphorylated at Serine-536 in rectal cancer with or without preoperative radiotherapy
Open this publication in new window or tab >>Expression of NF-κB p65 phosphorylated at Serine-536 in rectal cancer with or without preoperative radiotherapy
2011 (English)In: RADIOLOGY AND ONCOLOGY, ISSN 1318-2099, Vol. 45, no 4, 279-284 p.Article in journal (Refereed) Published
Abstract [en]

In the present study, we investigated NF-κB p65 phosphorylated at Serine-536 (phospho-Ser536-p65) in rectal cancer and its relationship to radiotherapy (RT) and clinicopathological and biological factors. Expression of phospho-Ser536-p65 was examined by using immunohistochemistry in 141 primary rectal cancers, 149 normal mucosa specimens and 48 metastases in the lymph nodes, from rectal cancer patients randomized to received RT or not. The expression of phospho-Ser536-p65 in the cytoplasm increased from normal mucosa to primary tumor (p<0.0001, for both RT and non-RT groups). The expression did not further increased from primary tumor to metastases in the either group (p>0.05). We found that the expression of phospho-Ser536-p65 was positively related to or tended to be positively related to expression of TEM1 (p=0.02), FXYD-3 (p=0.0006), PRL (p=0.02), p73 (p=0.048) and MAC30 (p=0.051) in the RT group but there were no such relationships in the non-RT group (p>0.05). The expression of the phospho-Ser536-p65 was not related to clinicopathological factors including survival (p>0.05). The increased expression of phospho-Ser536-p65 may be involved in rectal cancer development. After RT, the expression of NF-κB seems to be positively related to the biological factors which associated with more malignant features of tumors. However, we did not find that the phospho-Ser536-p65 was directly related to clinical response of RT.

Place, publisher, year, edition, pages
Versita, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53622 (URN)10.2478/v10019-011-0030-7 (DOI)000297064900006 ()
Note
Funding agencies|Swedish Cancer Foundation||Swedish Research Council||Health Research Council in the South-East of Sweden||Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2011-12-09Bibliographically approved

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