Ras modifies proliferation and invasiveness of cells expressing human papillomavirus oncoproteins.
Infection by human papillomavirus (HPV) is a major risk factor for human cervical carcinoma. However, the HPV infection alone is not sufficient for cancer formation. Cervical carcinogenesis is considered a multistep process accompanied by genetic alterations of the cell. Ras is activated in approximately 20% of human cancers, and it is related to the metastatic conversion of tumor cells. We investigated how Ras activation was involved in the malignant conversion of HPV-infected lesions. The active form of H-ras was introduced into human primary keratinocytes expressing the HPV type 18 (HPV18) oncoproteins E6 and/or E7. We analyzed the keratinocytes' growth potentials and found that the activation of the Ras pathway induced senescence-like growth arrest. Senescence could be eliminated by high-risk E7 expression, suggesting that the pRb pathway was important for Ras-induced senescence. Then we analyzed the effect of Ras activation on epidermis development by using an organotypic "raft" culture and found that the E7 and H-ras coexpressions conferred invasive potential on the epidermis. This invasiveness resulted from the upregulation of MT1-MMP and MMP9 by H-ras and E7, respectively, in which the activation of the MEK/extracellular signal-regulated kinase pathway was involved. These results indicated that the activation of Ras or the related signal pathways promoted the malignant conversion of HPV-infected cells.
Yoshida
Satoshi
S
Department of Viral Oncology, Laboratory of Gene Analysis, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Kajitani
Naoko
N
Satsuka
Ayano
A
Nakamura
Hiroyasu
H
Sakai
Hiroyuki
H
D018929:Cell Culture Techniques; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence; D016895:Culture Media, Serum-Free; D005260:Female; D005822:Genetic Vectors; D006367:HeLa Cells; D052161:Human papillomavirus 18 / Q000235:genetics / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology* / Q000821:virology; D007668:Kidney / Q000166:cytology; D008297:Male; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism; D009924:Organ Culture Techniques; D027383:Papillomaviridae / Q000235:genetics* / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000473:pathology; D018631:ras Proteins / Q000502:physiology*
D016895:Culture Media, Serum-Free; D009856:Oncogene Proteins, Viral; D016160:Retinoblastoma Protein; D018631:ras Proteins