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Radioresistant cervical cancer shows upregulation of the NHEJ proteins DNA-PKcs, Ku70 and Ku86.

Beskow C, Skikuniene J, Holgersson A, Nilsson B, Lewensohn R, Kanter L, Viktorsson K - Br. J. Cancer (2009)

Bottom Line: The formation of DNA double-strand breaks is considered to be critical for the radiotherapeutic effect.A correlation in DNA-PKcs expression between primary and residual tumours was found.The frequency of p21-positive cells was decreased (P=0.007) in residual tumours whereas no change in p53 or Mdm-2-positive cells were observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Solna, Stockholm SE-171 76, Sweden. Catharina.Beskow@ki.se

ABSTRACT

Background: Radiotherapy is central in the treatment of cervical cancer. The formation of DNA double-strand breaks is considered to be critical for the radiotherapeutic effect. The non-homologous end joining (NHEJ) proteins DNA-PKcs, Ku70 and Ku86 have a major role in repairing DNA lesions. The objective of this study was to analyse if the expression of DNA-PKcs, Ku70 and Ku86 and their downstream signalling molecules p53, p21 and Mdm-2 are altered in residual cervical tumours after radiotherapy.

Methods: Retrospective analysis of 127 patients with cervical cancer stage IB-IIA treated with preoperative radiotherapy and radical surgery, revealed residual tumour in the cervical specimen in 30 patients. In 22 cases tumour material from residual and corresponding primary tumour were retrieved and the expression of DNA-PKcs, Ku86, Ku70, p53, p21 and Mdm-2 were assessed by immunohistochemistry.

Results: Residual tumours showed increased frequency of DNA-PKcs (P=0.037), Ku70 (P=0.018), Ku86 (P=0.008) positive cells. A correlation in DNA-PKcs expression between primary and residual tumours was found. The frequency of p21-positive cells was decreased (P=0.007) in residual tumours whereas no change in p53 or Mdm-2-positive cells were observed.

Conclusion: Our results show that cervical carcinoma surviving radiotherapy have an increased DNA-PK expression. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of DNA-PK function may be part of a radioresistance mechanism within this tumour type.

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(A–C) Positive immunohistochemical staining of Ku70 (A) in poorly differentiated squamous cell carcinoma, Ku86 (B) in glassy cell adenocarcinoma and p21 (C) in moderately differentiated adenocarcinoma of the cervix. Immunoreactivity is noted in nuclei of the tumour cells. After radiotherapy an increased frequency of Ku70- and Ku86-positive tumour cells are seen parallel to a decrease in p21 positivity.
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fig1: (A–C) Positive immunohistochemical staining of Ku70 (A) in poorly differentiated squamous cell carcinoma, Ku86 (B) in glassy cell adenocarcinoma and p21 (C) in moderately differentiated adenocarcinoma of the cervix. Immunoreactivity is noted in nuclei of the tumour cells. After radiotherapy an increased frequency of Ku70- and Ku86-positive tumour cells are seen parallel to a decrease in p21 positivity.

Mentions: The percentages of cells staining positive for DNA-PKcs, Ku86 and Ku70 in primary biopsies and residual tumours for each patient are listed in Table 2. Residual tumours were found to display higher percentages of DNA-PKcs immunopositive cells (Mean±s.e.m.: 67.8±5.5), compared with the corresponding primary tumour biopsy (Mean±s.e.m.: 57.8±5.2) (mean diff=9.95, s.d.=20.4, P=0.037). Similarly, the frequency of cells staining positive for Ku70 and Ku86 were higher in residual than in primary tumours. Expression of Ku70 in primary tumours ranged from 48 to 95% (Mean±s.e.m.: 76.9±3.6) and from 51 to 98% (Mean±s.e.m.: 86.8±3.2) in residual tumours after RT (mean diff=9.91, s.d.=17.6, P=0.018) (Figure 1A). The expression of Ku86 varied between 0–98% (Mean±s.e.m. 66.7±5.4) in primary tumours, whereas in residual tumours the percentage of positive cells ranged from 55 to 100% (Mean±s.e.m.: 83.3±3.0) (mean diff=16.7, s.d.=26.1, P=0.008) (Figure 1B). Corresponding analysis yielded P-values of 0.029, 0.006 and 0.004, respectively. A correlation was observed between DNA-PKcs in primary and residual tumours (rho=0.55, P=0.010) (data not shown). In contrast, no correlations were found between primary and residual tumours for neither Ku70 (rho=0.126, P=0.586) nor Ku 86 (rho=0.323, P=0.154) proteins. All three proteins displayed a predominantly nuclear localisation. No overall differences in staining intensity could be detected when comparing primary and corresponding residual tumours for either DNA-PKcs or the Ku proteins. As seen in Table 2, there is a variation in positivity for the DNA-PK components among both the primary and residual tumour tissue. However, these differences in immunopositivity were not found to correlate with either clinical characteristics, that is, tumour size, histopathologic type or grade or with the RT regimen given.


Radioresistant cervical cancer shows upregulation of the NHEJ proteins DNA-PKcs, Ku70 and Ku86.

Beskow C, Skikuniene J, Holgersson A, Nilsson B, Lewensohn R, Kanter L, Viktorsson K - Br. J. Cancer (2009)

(A–C) Positive immunohistochemical staining of Ku70 (A) in poorly differentiated squamous cell carcinoma, Ku86 (B) in glassy cell adenocarcinoma and p21 (C) in moderately differentiated adenocarcinoma of the cervix. Immunoreactivity is noted in nuclei of the tumour cells. After radiotherapy an increased frequency of Ku70- and Ku86-positive tumour cells are seen parallel to a decrease in p21 positivity.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2736845&req=5

fig1: (A–C) Positive immunohistochemical staining of Ku70 (A) in poorly differentiated squamous cell carcinoma, Ku86 (B) in glassy cell adenocarcinoma and p21 (C) in moderately differentiated adenocarcinoma of the cervix. Immunoreactivity is noted in nuclei of the tumour cells. After radiotherapy an increased frequency of Ku70- and Ku86-positive tumour cells are seen parallel to a decrease in p21 positivity.
Mentions: The percentages of cells staining positive for DNA-PKcs, Ku86 and Ku70 in primary biopsies and residual tumours for each patient are listed in Table 2. Residual tumours were found to display higher percentages of DNA-PKcs immunopositive cells (Mean±s.e.m.: 67.8±5.5), compared with the corresponding primary tumour biopsy (Mean±s.e.m.: 57.8±5.2) (mean diff=9.95, s.d.=20.4, P=0.037). Similarly, the frequency of cells staining positive for Ku70 and Ku86 were higher in residual than in primary tumours. Expression of Ku70 in primary tumours ranged from 48 to 95% (Mean±s.e.m.: 76.9±3.6) and from 51 to 98% (Mean±s.e.m.: 86.8±3.2) in residual tumours after RT (mean diff=9.91, s.d.=17.6, P=0.018) (Figure 1A). The expression of Ku86 varied between 0–98% (Mean±s.e.m. 66.7±5.4) in primary tumours, whereas in residual tumours the percentage of positive cells ranged from 55 to 100% (Mean±s.e.m.: 83.3±3.0) (mean diff=16.7, s.d.=26.1, P=0.008) (Figure 1B). Corresponding analysis yielded P-values of 0.029, 0.006 and 0.004, respectively. A correlation was observed between DNA-PKcs in primary and residual tumours (rho=0.55, P=0.010) (data not shown). In contrast, no correlations were found between primary and residual tumours for neither Ku70 (rho=0.126, P=0.586) nor Ku 86 (rho=0.323, P=0.154) proteins. All three proteins displayed a predominantly nuclear localisation. No overall differences in staining intensity could be detected when comparing primary and corresponding residual tumours for either DNA-PKcs or the Ku proteins. As seen in Table 2, there is a variation in positivity for the DNA-PK components among both the primary and residual tumour tissue. However, these differences in immunopositivity were not found to correlate with either clinical characteristics, that is, tumour size, histopathologic type or grade or with the RT regimen given.

Bottom Line: The formation of DNA double-strand breaks is considered to be critical for the radiotherapeutic effect.A correlation in DNA-PKcs expression between primary and residual tumours was found.The frequency of p21-positive cells was decreased (P=0.007) in residual tumours whereas no change in p53 or Mdm-2-positive cells were observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Solna, Stockholm SE-171 76, Sweden. Catharina.Beskow@ki.se

ABSTRACT

Background: Radiotherapy is central in the treatment of cervical cancer. The formation of DNA double-strand breaks is considered to be critical for the radiotherapeutic effect. The non-homologous end joining (NHEJ) proteins DNA-PKcs, Ku70 and Ku86 have a major role in repairing DNA lesions. The objective of this study was to analyse if the expression of DNA-PKcs, Ku70 and Ku86 and their downstream signalling molecules p53, p21 and Mdm-2 are altered in residual cervical tumours after radiotherapy.

Methods: Retrospective analysis of 127 patients with cervical cancer stage IB-IIA treated with preoperative radiotherapy and radical surgery, revealed residual tumour in the cervical specimen in 30 patients. In 22 cases tumour material from residual and corresponding primary tumour were retrieved and the expression of DNA-PKcs, Ku86, Ku70, p53, p21 and Mdm-2 were assessed by immunohistochemistry.

Results: Residual tumours showed increased frequency of DNA-PKcs (P=0.037), Ku70 (P=0.018), Ku86 (P=0.008) positive cells. A correlation in DNA-PKcs expression between primary and residual tumours was found. The frequency of p21-positive cells was decreased (P=0.007) in residual tumours whereas no change in p53 or Mdm-2-positive cells were observed.

Conclusion: Our results show that cervical carcinoma surviving radiotherapy have an increased DNA-PK expression. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of DNA-PK function may be part of a radioresistance mechanism within this tumour type.

Show MeSH
Related in: MedlinePlus