TY - JOUR
T1 - Novel K6-K14 keratin fusion enhances cancer stemness and aggressiveness in oral squamous cell carcinoma
AU - Tsai, Fuu Jen
AU - Lai, Ming Tsung
AU - Cheng, Jack
AU - Chao, Stev Chun Chin
AU - Korla, Praveen Kumar
AU - Chen, Hui Jye
AU - Lin, Chung Ming
AU - Tsai, Ming Hsui
AU - Hua, Chun Hung
AU - Jan, Chia Ing
AU - Jinawath, Natini
AU - Wu, Chia Chen
AU - Chen, Chih Mei
AU - Kuo, Brian Yu Ting
AU - Chen, Li Wen
AU - Yang, Jacky
AU - Hwang, Tritium
AU - Sheu, Jim Jinn Chyuan
N1 - Publisher Copyright:
© 2019, Springer Nature Limited.
PY - 2019/6/27
Y1 - 2019/6/27
N2 - Keratin intermediate filament (IF) is one component of cellular architectures, which provides necessary mechanical support to conquer environmental stresses. Recent findings reveal its involvement in mechano-transduction and the associated stem cell reprogramming, suggesting the possible roles in cancer development. Here, we report t(12;17)(q13.13;q21.2) chromosomal rearrangement as the most common fusion event in OSCC, resulting in a variety of inter-keratin fusions. Junction site mapping verified 9 in-frame K6-K14 variants, three of which were correlated with lymph node invasion, late tumor stages (T3/T4) and shorter disease-free survival times. When expressed in OSCC cells, those fusion variants disturbed wild-type K14 organization through direct interaction or aggregate formation, leading to perinuclear structure loss and nuclear deformation. Protein array analyses showed the ability of K6-K14 variant 7 (K6-K14/V7) to upregulate TGF-β and G-CSF signaling, which contributed to cell stemness, drug tolerance, and cell aggressiveness. Notably, K6-K14/V7-expressing cells easily adapted to a soft 3-D culture condition in vitro and formed larger, less differentiated tumors in vivo. In addition to the anti-mechanical-stress activity, our data uncover oncogenic functionality of novel keratin filaments caused by gene fusions during OSCC development.
AB - Keratin intermediate filament (IF) is one component of cellular architectures, which provides necessary mechanical support to conquer environmental stresses. Recent findings reveal its involvement in mechano-transduction and the associated stem cell reprogramming, suggesting the possible roles in cancer development. Here, we report t(12;17)(q13.13;q21.2) chromosomal rearrangement as the most common fusion event in OSCC, resulting in a variety of inter-keratin fusions. Junction site mapping verified 9 in-frame K6-K14 variants, three of which were correlated with lymph node invasion, late tumor stages (T3/T4) and shorter disease-free survival times. When expressed in OSCC cells, those fusion variants disturbed wild-type K14 organization through direct interaction or aggregate formation, leading to perinuclear structure loss and nuclear deformation. Protein array analyses showed the ability of K6-K14 variant 7 (K6-K14/V7) to upregulate TGF-β and G-CSF signaling, which contributed to cell stemness, drug tolerance, and cell aggressiveness. Notably, K6-K14/V7-expressing cells easily adapted to a soft 3-D culture condition in vitro and formed larger, less differentiated tumors in vivo. In addition to the anti-mechanical-stress activity, our data uncover oncogenic functionality of novel keratin filaments caused by gene fusions during OSCC development.
UR - http://www.scopus.com/inward/record.url?scp=85062910754&partnerID=8YFLogxK
U2 - 10.1038/s41388-019-0781-y
DO - 10.1038/s41388-019-0781-y
M3 - 文章
C2 - 30867567
AN - SCOPUS:85062910754
SN - 0950-9232
VL - 38
SP - 5113
EP - 5126
JO - Oncogene
JF - Oncogene
IS - 26
ER -
