The role of cyclins and cyclins inhibitors in the multistep process of HPV-associated cervical carcinoma.
BACKGROUND
Human papillomavirus (HPV) types 16 and 18 are associated with cervical carcinogenesis. This is possibly achieved through an interaction between HPV oncogenic proteins and some cell cycle regulatory genes. However, the exact pathogenetic mechanisms are not well defined yet.


METHODS
We investigated 110 subjects (43 invasive squamous cell carcinoma (ISCC), 38 CIN III, 11 CIN II, 18 CIN I) confirmed to be positive for HPV16 and/or 18 as well as 20 normal cervical tissue (NCT) samples for abnormal expression of cyclin D1, cyclin E, CDK4, cyclin inhibitors (p21 (waf), p27, p16 (INK4A)) and Ki-67 using immunohistochemistry and differential PCR techniques.


RESULTS
There was a significant increase in the expression of Ki-67, cyclin E, CDK4, p16 (INK4A) (p=0.003, 0.001, 0.001) and a significant decrease in p27 (Kip1) from NCT to ISCC (p=0.003). There was a significant correlation between altered expression of p27 (KIP1) and p16(INK4A) (p<0.001), cyclin D1 and CDK4 (p=0.001), cyclin E and p27 (Kip1) (p=0.011) in all studied groups. In ISCC, there was significant relationship between standard clinicopathological prognostic factors and high Ki-67 index , increased cyclin D1 and cyclin E, reduced p27 (Kip1) and p21 (waf).


CONCLUSIONS
1) Aberrations involving p27 (KIP1), cyclin E, CDK4 and p16 (INK4A) are considered early events in HPV 16 and 18-associated cervical carcinogenesis (CINI & II), whereas cyclin D1 aberrations are late events (CINIII & ISCC) 2) Immunohistochemical tests for p16 (INK4A) and cyclin E could help in early diagnosis of cervical carcinoma 3) Only FIGO stage, cyclin D1, p27 (Kip1) and Ki-67 are independent prognostic factors that might help in predicting outcome of cervical cancer patients.
Bahnassy
Abeer A
AA
The Departments of Pathology, National Cancer Institute, Cairo, Egypt. chaya2000@hotmail.com
Zekri
Abdel Rahman N
AR
Alam El-Din
Hanaa M
HM
Aboubakr
Amany A
AA
Kamel
Khaled
K
El-Sabah
Mahmoud T
MT
Mokhtar
Nadia M
NM
D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019940:Genes, bcl-1; D019942:Genes, p16; D052162:Human papillomavirus 16; D052161:Human papillomavirus 18; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D030361:Papillomavirus Infections / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
D019927:Cyclin E; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; D019394:Ki-67 Antigen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases