Molecular basis of posttransplant squamous cell carcinoma: the potential role of cyclosporine a in carcinogenesis.
Cyclosporine (CSA) is a widely used immunosuppressive agent, predominantly for transplant patients. It is well recognized that transplant patients are prone to develop squamous carcinoma of the skin and mucosa, and this high incidence of squamous carcinoma in the transplant population cannot be explained by immunosuppression alone. We hypothesize that CSA may play a significant role in the transformation of normal epidermal squamous cells to carcinoma. CSA is a specific ligand for calcineurin, a ubiquitously expressed cellular serine/threonine phosphatase, that plays important roles in the immune system and cardiac muscles. Using global gene-profiling methods, we studied the short-time CSA effect on the squamous cell line (SCC-015) using Affymetrix human gene chips (Human U133, 2.0 plus chip). Multiple groups of genes were identified to be responsive to CSA treatment, including many genes of unknown functions. We then used reverse transcriptase-polymerase chain reaction and immunoblot analyses to selectively confirm the results from the chips analyses with emphasis on the regulatory molecules important for cellular functions of apoptosis, DNA damage repair, and cellular transformation. This global gene-profiling study indicated that CSA not only functions as an immunosuppressant on the immune system, but also activates/inhibits a wide array of genes important for cell-cycle regulation, apoptosis, and oncogene/tumor-suppressor activation. These functions of CSA on skin and mucosa systems at the molecular level are likely important in the pathogenesis of squamous carcinoma in transplant patients.
Tiu
Jeremy
J
Department of Otolaryngology, West Virginia University, Morgantown, West Virginia 25526, USA.
Li
Hongli
H
Rassekh
Christopher
C
van der Sloot
Paul
P
Kovach
Rodney
R
Zhang
Peilin
P
D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000473:pathology; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D008967:Molecular Biology; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D016378:Tissue Transplantation / Q000009:adverse effects / Q000379:methods; D014181:Transplantation Immunology / Q000187:drug effects*
D007166:Immunosuppressive Agents; D016572:Cyclosporine