Inhibition of tumorigenicity and enhancement of radiochemosensitivity in head and neck squamous cell cancer-derived ALDH1-positive cells by knockdown of Bmi-1.
Bmi-1, a member of the Polycomb family of transcriptional repressors, is essential for maintaining the self-renewal abilities of adult stem cells. Bmi-1 has been demonstrated to play a role in tumorigenesis in head and neck squamous cell carcinomas (HNSCCs). A recent study has further suggested that ALDH1 may be considered to be a putative marker for HNSCC-derived cancer stem cells. However, the role that Bmi-1 plays in HNSCC-derived ALDH1-positive cells (HNSCC-ALDH1(+)) has yet to be determined. In this study, we demonstrated that HNSCC-ALDH1(+) cells possess tumor initiating properties, are capable of self-renewal, and express higher levels of Bmi-1 as compared to HNSCC-ALDH1(-) cells. To further explore the functional role of Bmi-1 in HNSCC-ALDH1(+) cells, we used a lentiviral vector expressing shRNA to knock down Bmi-1 expression (sh-Bmi-1) in HNSCC-ALDH1(+) cells. Silencing of Bmi-1 significantly enhanced the sensitivity of HNSCC-ALDH1(+) cells to chemoradiation and increased the degree of chemoradiation-mediated apoptosis that occurred. Importantly, knockdown of Bmi-1 increased the effectiveness of radiotherapy and led to the inhibition of tumor growth in nude mice transplanted with HNSCC-ALDH1(+) cells. Kaplan-Meier survival analysis indicated that the mean survival rate of HNSCC-ALDH1(+) tumor-bearing immunocompromised mice treated with radiotherapy was significantly improved by treatment with sh-Bmi-1 as well. In summary, these results suggest that Bmi-1 is a potential target for increasing the sensitivity of HNSCC cancer stem cells to chemoradiotherapy.
Chen
Yu-Chih
YC
Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
Chang
Charn-Jung
CJ
Hsu
Han-Shui
HS
Chen
Yi-Wei
YW
Tai
Lung-Kuo
LK
Tseng
Ling-Ming
LM
Chiou
Guang-Yuh
GY
Chang
Shih-Ching
SC
Kao
Shou-Yen
SY
Chiou
Shih-Hwa
SH
Lo
Wen-Liang
WL
D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D050697:Retinal Dehydrogenase; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase