Methylation status of insulin-like growth factor-binding protein 7 concurs with the malignance of oral tongue cancer.

Abstract

BACKGROUND:

Aberrant insulin-like growth factor-binding protein 7 (IGFBP-7) expression has been found in various cancers such as prostate, breast, and colon. IGFBP-7 induced the apoptosis of tumor and potentially predicted the clinical outcome in some cancers is further demonstrated. This study investigates the causes and underlying mechanisms of aberrant IGFBP-7 expression in unravelling head and neck squamous cell carcinoma (HNSCC).

METHODS:

A total of 47 oral tongue cancer patient samples were primarily analyzed for the methylation status in 5' region of IGFBP-7 by methylation-specific PCR (MS-PCR). Subsequently the invasion, overexpression, and knockdown of IGFBP-7 in the HNSCC A253 invasive subpopulation were employed to examine the effect of IGFBP-7. The epithelial-mesenchymal transition (EMT) marker genes and AKT/GSK3β/β-catenin signaling were further evaluated by Western blot for the understanding the role of aberrant IGFBP-7 expression and thereof putative mechanism.

RESULTS:

EMT expressed in the invasive subpopulation of HNSCC cell lines (A253 and RPMI 2650) was contemporary with the down-regulation of IGFBP-7. After treatment with 5-AZA-2' deoxycytidine, the de-methylated CpG sites in the 5' region of IGFBP-7 were observed and IGFBP-7 mRNA expression was also restored. Accordingly, re-expression IGFBP-7 in invasive subpopulation of A253 could induce the mesenchymal-epithelial transition (MET) and concurrently inhibited the cell invasion. Moreover, IGFBP-7 methylation status of 47 oral tongue tumors showed a positive correlation to invasive depth of the tumor, loco-regional recurrence, and cancer sequence.

CONCLUSIONS:

IGFBP-7 can alter EMT relative marker genes and suppress cell invasion in A253 cell through AKT/GSK3β/β-catenin signaling. The epigenetic control of IGFBP-7 in the invasion and metastasis of HNSCC was reported, suggesting that IGFBP-7 could be a prognostic factor for the probability of invasion and a therapeutic remedy.

• Authors: Li-Hsuen Chen, Dai-Wei Liu, Junn-Liang Chang, Peir-Rong Chen, Lee-Ping Hsu, Hon-Yi Lin, Yu-Fu Chou, Chia-Fong Lee, Miao-Chun Yang, Yu-Hsuan Wen, Wen-Lin Hsu, Ching-Feng Weng
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 34 Pg. 20 (Feb 24 2015) ISSN: 1756-9966 [Electronic] England
• PMID: 25880247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin-Like Growth Factor Binding Proteins
• insulin-like growth factor binding protein-related protein 1
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Adult
• Cell Line, Tumor
• DNA Methylation
• Down-Regulation
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Insulin-Like Growth Factor Binding Proteins (genetics, metabolism)
• Male
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Prognosis
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Tongue Neoplasms (genetics, metabolism, mortality, pathology, therapy)
• Tumor Burden