TY - JOUR
T1 - Wnt/β-catenin-C-kit axis may play a role in adenoid cystic carcinoma prognostication
AU - Fujii, Shinsuke
AU - Hasegawa, Kana
AU - Maehara, Takashi
AU - Kurppa, Kari J.
AU - Heikinheimo, Kristiina
AU - Warner, Kristy A.
AU - Maruyama, Satoshi
AU - Tajiri, Yudai
AU - Nör, Jacques E.
AU - Tanuma, Jun ichi
AU - Kawano, Shintaro
AU - Kiyoshima, Tamotsu
N1 - Publisher Copyright:
© 2024 Elsevier GmbH
PY - 2024/2
Y1 - 2024/2
N2 - Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still relatively poor. Although several gene abnormalities, such as fusions involving MYB or MYBL1 oncogenes and the transcription factor gene NFIB, and overexpression of KIT have been reported in ACC, their precise functions in the pathogenesis of ACC remain unclear. We recently demonstrated that the elevated expression of Semaphorin 3A (SEMA3A), specifically expressed in myoepithelial neoplastic cells, might function as a novel oncogene-related molecule to enhance cell proliferation through activated AKT signaling in 9/10 (90%) ACC cases. In the current study, the patient with ACC whose tumor was negative for SEMA3A in the previous study, revisited our hospital with late metastasis of ACC to the cervical lymph node eight years after surgical resection of the primary tumor. We characterized this recurrent ACC, and compared it with the primary ACC using immunohistochemical methods. In the recurrent ACC, the duct lining epithelial cells, not myoepithelial neoplastic cells, showed an elevated Ki-67 index and increased cell membrane expression of C-kit, along with the expression of phosphorylated ERK. Late metastasis ACC specimens were not positive for β-catenin and lymphocyte enhancer binding factor 1 (LEF1), which were detected in the nuclei of perineural infiltrating cells in primary ACC cells. In addition, experiments with the GSK-3 inhibitor revealed that β-catenin pathway suppressed not only KIT expression but also proliferation of ACC cells. Moreover, stem cell factor (SCF; also known as KIT ligand, KITL) induced ERK activation in ACC cells. These results suggest that inactivation of Wnt/β-catenin signaling may promote C-kit-ERK signaling and cell proliferation of in metastatic ACC.
AB - Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still relatively poor. Although several gene abnormalities, such as fusions involving MYB or MYBL1 oncogenes and the transcription factor gene NFIB, and overexpression of KIT have been reported in ACC, their precise functions in the pathogenesis of ACC remain unclear. We recently demonstrated that the elevated expression of Semaphorin 3A (SEMA3A), specifically expressed in myoepithelial neoplastic cells, might function as a novel oncogene-related molecule to enhance cell proliferation through activated AKT signaling in 9/10 (90%) ACC cases. In the current study, the patient with ACC whose tumor was negative for SEMA3A in the previous study, revisited our hospital with late metastasis of ACC to the cervical lymph node eight years after surgical resection of the primary tumor. We characterized this recurrent ACC, and compared it with the primary ACC using immunohistochemical methods. In the recurrent ACC, the duct lining epithelial cells, not myoepithelial neoplastic cells, showed an elevated Ki-67 index and increased cell membrane expression of C-kit, along with the expression of phosphorylated ERK. Late metastasis ACC specimens were not positive for β-catenin and lymphocyte enhancer binding factor 1 (LEF1), which were detected in the nuclei of perineural infiltrating cells in primary ACC cells. In addition, experiments with the GSK-3 inhibitor revealed that β-catenin pathway suppressed not only KIT expression but also proliferation of ACC cells. Moreover, stem cell factor (SCF; also known as KIT ligand, KITL) induced ERK activation in ACC cells. These results suggest that inactivation of Wnt/β-catenin signaling may promote C-kit-ERK signaling and cell proliferation of in metastatic ACC.
KW - ACC
KW - C-kit
KW - Late metastasis
KW - Tongue
KW - Wnt/β-catenin
UR - http://www.scopus.com/inward/record.url?scp=85183500141&partnerID=8YFLogxK
U2 - 10.1016/j.prp.2024.155148
DO - 10.1016/j.prp.2024.155148
M3 - Article
C2 - 38277753
AN - SCOPUS:85183500141
SN - 0344-0338
VL - 254
JO - Pathology Research and Practice
JF - Pathology Research and Practice
M1 - 155148
ER -