Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells.
Our effort to identify novel drug-resistant genes in cyclophosphamide-resistant EMT6 mouse mammary tumors led us to the identification of SPF45. Simultaneously, other groups identified SPF45 as a component of the spliceosome that is involved in alternative splicing. We isolated the human homologue and examined the normal human tissue expression, tumor expression, and the phenotype caused by overexpression of human SPF45. Our analyses revealed that SPF45 is expressed in many, but not all, normal tissues tested with predominant expression in normal ductal epithelial cells of the breast, liver, pancreas, and prostate. Our analyses using tissue microarrays and sausages of tumors indicated that SPF45 is highly expressed in numerous carcinomas including bladder, breast, colon, lung, ovarian, pancreatic, and prostate. Interestingly, this study revealed that overexpression of SPF45 in HeLa, a cervical carcinoma cell line, resulted in drug resistance to doxorubicin and vincristine, two chemotherapeutic drugs commonly used in cancer. To our knowledge, this is the first study showing tumor overexpression of an alternate splicing factor resulting in drug resistance.
Sampath
Janardhan
J
Cancer Research Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Long
Pandy R
PR
Shepard
Robert L
RL
Xia
Xiaoling
X
Devanarayan
Viswanath
V
Sandusky
George E
GE
Perry
William L
WL
Dantzig
Anne H
AH
Williamson
Mark
M
Rolfe
Mark
M
Moore
Robert E
RE
D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004848:Epithelium / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D016133:Polymerase Chain Reaction; D040081:Protein Array Analysis; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
C121693:RBM17 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins