Detection and Functional Characterization of KRT fusions in Oral Squamous Cell Carcinoma

• Main Authors: Chia-Chen Wu, 吳佳真
• Other Authors: Jim Jinn-Chyuan Sheu
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/u4x66s

碩士 === 國立中山大學 === 生物醫學研究所 === 104 === Keratin cytoskeleton proteins form intermediate filaments in epithelial cells to regulate cell shape, mobility, membrane trafficking and cellular signaling. Although keratin-6 (K6) and -14 (K14) are highly expressed in certain squamous cell carcinomas and have been suggested as tumor markers, molecular mechanisms of how keratins contribute to cancer development still remain elusive. In early studies, we demonstrated novel K6-K14 chimeras in oral squamous cell carcinomas (OSCCs) by pair-ended transcriptome sequencing and subsequent validation by fluorescence in situ hybridization and junction site mapping. Two unique fusion types (type-1 and type-2) were identified with a total of 23 in-frame fusion variants verified in OSCCs. Clinical screening confirmed high detection rate of K6-K14 fusions in tumor samples: 33% for type-1 and 25% for type-2. To know the cause for the keratin fusions, OSCC cells were treated with arecoline, 4NQO, alcohol, and the combinations of these three well-known OSCC carcinogens. Our data found acrecoline as the promoter to accelerate the induction of K6-K14 fusions by 4NQO. Functional study further confirmed that the type-2 fusions can increase cell proliferation, migration and invasion via EMT and cancer stem cell formation. Our study thus uncovered a novel mechanism involved in carcinogenesis by keratin fusions.