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Functional Characterization of Novel Mutations Affecting S urvivin ( BIRC 5)‐Mediated Therapy Resistance in Head and Neck Cancer Patients
Author(s) -
Knauer Shirley K.,
Unruhe Britta,
Karczewski Sarah,
Hecht Rouven,
Fetz Verena,
Bier Carolin,
Friedl Sandra,
Wollenberg Barbara,
Pries Ralph,
Habtemichael Negusse,
Heinrich UlfRüdiger,
Stauber Roland H.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22249
Subject(s) - survivin , cancer research , biology , cancer , head and neck squamous cell carcinoma , cancer cell , nuclear export signal , microbiology and biotechnology , cell nucleus , head and neck cancer , cytoplasm , genetics
S urvivin ( BIRC 5) is an acknowledged cancer therapy‐resistance factor and overexpressed in head and neck squamous cell carcinomas ( HNSCC ). Driven by its nuclear export signal ( NES ), S urvivin shuttles between the nucleus and the cytoplasm, and is detectable in both cellular compartments in tumor biopsies. Although predominantly nuclear S urvivin is considered a favorable prognostic disease marker for HNSCC patients, the underlying molecular mechanisms are not resolved. Hence, we performed immunohistochemical and mutational analyses using laser capture microdissection on HNSCC biopsies from patients displaying high levels of nuclear S urvivin. We found somatic BIRC 5 mutations, c.278T>C (p.Phe93Ser), c.292C>T (p.Leu98Phe), and c.288A>G (silent), in tumor cells, but not in corresponding normal tissues. Comprehensive functional characterization of the S urvivin mutants by ectopic expression and microinjection experiments revealed that p.Phe93Ser, but not p.Leu98Phe inactivated S urvivin's NES , resulted in a predominantly nuclear protein, and attenuated S urvivin's dual cytoprotective activity against chemoradiation‐induced apoptosis. Notably, in xenotransplantation studies, HNSCC cells containing the p.Phe93Ser mutation responded significantly better to cisplatin‐based chemotherapy. Collectively, our results underline the disease relevance of S urvivin's nucleocytoplasmic transport, and provide first evidence that genetic inactivation of S urvivin's NES may account for predominantly nuclear S urvivin and increased therapy response in cancer patients.