癌基因prkcisox与肺鳞癌精要.pdf

Cancer Cell Article The PRKCI and SOX2 Oncogenes Are Coampli?ed and Cooperate to Activate Hedgehog Signaling in Lung Squamous Cell Carcinoma Verline Justilien, 1Michael P. Walsh, 1Syed A. Ali, 1E. Aubrey Thompson, 1Nicole R. Murray, 1and Alan P. Fields 1 , * 1Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA *Correspondence: ?elds.******@ http://dx./. SUMMARY We report that two oncogenes coampli?ed on chromosome 3q26, PRKCI and SOX2 , cooperate to drive a stem-like phenotype in lung squamous cell carcinoma (). Protein kinase C i (PKC i) phosphorylates SOX2, a master transcriptional regulator of stemness, and recruits it to the promoter of Hedgehog (Hh) acyltransferase ( HHAT ) that catalyzes the rate-limiting step in Hh ligand production. PKC i-mediated SOX2 phosphorylation is required for HHAT promoter occupancy, HHAT expression, and maintenance of a stem-like phenotype. Primary tumors coordinately overexpress PKC i, SOX2, and HHAT and require PKC i-SOX2-HHAT signaling to maintain a stem-like phenotype. Thus, PKC iand SOX2 are ically, biochemically, and functionally linked in , and together they drive tumorigenesis by establishing a cell-autonomous Hh signaling axis. INTRODUCTION Lung cancer is the major cause of cancer death, with a 5-year- survival rate of 16% ( Siegel et al., 2012 ). Non-small cell lung cancer (NSCLC) accounts for ?80% of lung cancer cases and is subdivided into adenocarcinoma (LAC), squamous cell carcinoma (), and large cell carcinoma (LCLC). Distinct histologies, ic and ic changes, and sites of origin characterize NSCLC subtypes, suggesting they may have unique responses to therapy. Recent therapies targeting pathways active in NSCLC subtypes have resulted in encour- aging new treatments for LAC driven by EGFR or EML4-ALK mutations. However, few advances have resulted in better treatment options for , a carcinoma that accounts for 30% of all lung cancer cases. Thus, there is a