Major vault protein may affect nonhomologous end-joining repair and apoptosis through Ku70/80 and bax downregulation in cervical carcinoma tumors.
OBJECTIVE
We investigated the relationship between major vault protein (MVP) expression, the nonhomologous end-joining (NHEJ) repair gene Ku70/80, and related genes involved in the regulation of apoptosis and proliferation to shed light on the possible causes of genetic instability, tumor progression, and resistance to oncologic treatment in patients with clinical cervical cancer.


METHODS
One hundred sixteen consecutive patients with localized cervix carcinoma were prospectively included in this study from July 1997 to Dec 2003. Patients were staged according to the tumor, node, metastasis (TNM) classification. Forty patients had Stage I disease, 45 had Stage II, and 31 had Stage III/IVA. Most patients had squamous tumors (98 cases) and Grades II (52 cases) and III (45 cases) carcinomas. Expression of MVP, Ku70/80, Insulin-Like Growth Factor-1 receptor (IGF-1R), BCL2-associated X protein (BAX), B-cell CLL/lymphoma 2 (BCL-2), p53, and Ki67 was studied by using immunohistochemistry in paraffin-embedded tumor tissue.


RESULTS
Tumors overexpressing MVP (65 of 116 cases) showed low levels of Ku70/80 (p = 0.013) and BAX expression (p < 0.0001). Furthermore, low Ku70/80 expression was strongly related to suppressed BAX (p < 0.001) and, to a lesser extent, upregulated BCL-2 (p = 0.042), altered p53 (p = 0.038), and increased proliferation (p = 0.002).


CONCLUSIONS
We hypothesize that an early regulatory mechanism favors homologous or NHEJ repair at first, mediated by vaults along with other factors yet to be elucidated. If vaults are overexpressed, NHEJ repair may be suppressed by means of several mechanisms, with resultant genomic instability. These mechanisms may be associated with the decision of damaged cells to survive and proliferate, favoring tumor progression and reducing tumor response to oncologic treatment through the development of resistant cell phenotypes. Additional clinical studies are necessary to test this hypothesis.
Lloret
Marta
M
Radiation Oncology Department, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain. mllosae@hotmail.com
Lara
Pedro Carlos
PC
Bordón
Elisa
E
Fontes
Fausto
F
Rey
Agustin
A
Pinar
Beatriz
B
Falcón
Orlando
O
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation; D043171:Chromosomal Instability / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D000072200:Ku Autoantigen; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D011446:Prospective Studies; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099187:Major Vault Protein
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D000072200:Ku Autoantigen; D009363:Neoplasm Proteins; D017526:Receptor, IGF Type 1; D016159:Tumor Suppressor Protein p53; D020394:Vault Ribonucleoprotein Particles; D051028:bcl-2-Associated X Protein; D000099187:Major Vault Protein; C000606509:Xrcc6 protein, human