C-Met pathway promotes self-renewal and tumorigenecity of head and neck squamous cell carcinoma stem-like cell.
OBJECTIVE
Increasing evidence indicates that a rare subpopulation of cancer cells, namely, cancer stem cells (CSCs), is the primary cause of tumorigenesis in some tumor types, including head and neck squamous cell carcinoma (HNSCC). Hepatocyte growth factor (HGF) and its receptor, c-Met, are involved in tongue development and carcinogenesis of HNSCC. Here, we investigated whether activation of HGF/c-Met signaling influences the stem cell traits of HNSCC CSC.


METHODS
After HGF treatment, we assessed the sphere-forming capacity and stem cell marker expression in HNSCC stem-like cells compared with the respective control cells in vitro. In addition, we evaluated the effect of c-Met knockdown on the sphere-forming capacity, stem cell marker expression, and cisplatin chemosensitivity of HNSCC stem-like cells in vitro. Furthermore, we evaluated the inhibitory effect of c-Met knockdown on the capacity of HNSCC stem-like cells to initiate tumor growth in the orthotopic mouse model.


RESULTS
HGF treatment promoted the sphere-forming capacity of HNSCC stem-like cells and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. Transcriptional levels of c-Met was increased in cells with high aldehyde dehydrogenase (ALDH) 1 activity, a putative marker for HNSCC stem-like cells, compared to cells with low activity. In contrast, knockdown of c-Met attenuated the sphere-forming capacity and stem cell markers expression in HNSCC stem-like cells, and augmented cisplatin chemosensitivity by decreased side population cells and suppression of an ABCG2 transporter gene. Furthermore, knockdown of c-Met in HNSCC stem-like cells inhibits tumor formation of mice in a xenograft model and increases mice survival.


CONCLUSIONS
Our results suggest that inhibition of the c-Met pathway could serve as a potent therapeutic strategy to target HNSCC stem-like cells.
Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul 143-752, Republic of Korea. Electronic address: yclim69@hanmail.net.
Young Chang
YC
Lim
Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul 143-752, Republic of Korea.
Hyun Jung
HJ
Kang
Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul 143-752, Republic of Korea.
Jung Hwa
JH
Moon
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D017228:Hepatocyte Growth Factor; D000444:Aldehyde Dehydrogenase; D019859:Proto-Oncogene Proteins c-met; D002945:Cisplatin
Head and neck neoplasm; Met protein; Neoplastic stem cells