Reduced Apaf-1 expression in human cutaneous melanomas.
Malignant melanoma is a life-threatening skin cancer due to its highly metastatic character and resistance to radio- and chemotherapy. It is believed that the ability to evade apoptosis is the key mechanism for the rapid growth of cancer cells. However, the exact mechanism for failure in the apoptotic pathway in melanoma cells is unclear. p53, the most frequently mutated tumour suppressor gene in human cancers, is a key apoptosis inducer. However, p53 mutation is only found in 15-20% of melanoma biopsies. Recently, it was found that Apaf-1, a downstream target of p53, is inactivated in metastatic melanoma. Specifically, loss of heterozygosity (LOH) of the Apaf-1 gene was found in 40% of metastatic melanoma. To determine if loss of Apaf-1 expression is indeed involved in melanoma progression, we employed the tissue microarray technology and examined Apaf-1 expression in 70 human primary malignant melanoma biopsies by immunohistochemistry. Our data showed that Apaf-1 expression is significantly reduced in melanoma cells compared with normal nevi (chi(2)=6.02, P=0.014). Our results also revealed that loss of Apaf-1 was not associated with the tumour thickness, ulceration or subtype, patient's gender, age and 5-year survival. In addition, our in vitro apoptosis assay revealed that overexpression of Apaf-1 can sensitise melanoma cells to anticancer drug treatment. Taken together, our data indicate that Apaf-1 expression is significantly reduced in human melanoma and that Apaf-1 may serve as a therapeutic target in melanoma.
1Department of Medicine, Division of Dermatology, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, BC, Canada V6H 3Z6.
D L
DL
Dai
M
M
Martinka
J A
JA
Bush
G
G
Li
D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D045744:Cell Line, Tumor; D002470:Cell Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009506:Nevus / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D011506:Proteins