Wnt/-catenin pathway activation and silencing of the APC gene in HPV-positive human cervical cancer-derived cells
Por:
Ayala-Calvillo, Erick, Humberto Mojica-Vazquez, Luis, Garcia-Carranca, Alejandro, Gonzalez-Maya, Leticia
Publicada:
1 ene 2018
Resumen:
Although persistent infections with high-risk human papilloma virus
(HPV) constitute the most significant cofactor for the development of
cervical cancer, they are insufficient on their own. Mutations or
epigenetic inactivation of the tumor suppressor adenomatous polyposis
coli (APC), the two acting as prominent oncogenic mechanisms in a number
of types of cancer, are frequently associated with aberrant activation
of the Wnt/-catenin pathway. According to these observations, it was
hypothesized that APC alteration may lead to -catenin deregulation and
the abnormal expression of direct targets of the Wnt pathway in
HPV-infected cervical cancer cells. The present study confirmed that the
stabilization of -catenin correlates with enhanced transcriptional
activity of the -catenin/T-cell factor complex in cervical cancer cell
lines. Sequence analysis of the hot-spot' in the mutation cluster region
did not exhibit genetic alterations that may be associated with APC gene
inactivation. In addition, it was identified that there was a good
correlation with the hypermethylation status of the APC promoter 1A and
the abnormal accumulation of endogenous -catenin in cell lines and
biopsies infected with HPV16, although not HPV18. Removal of the
epigenetic markers led to an increase in APC levels and a reduction of
-catenin expression in two transcriptional targets of the Wnt pathway:
Matrix metalloproteinase-7 and vascular endothelial growth factor. The
present study suggested that the increase in Wnt activity in certain
cervical cancer-derived cells may be associated with an alteration in
the methylation status of the APC gene promoter 1A.
Filiaciones:
Ayala-Calvillo, Erick:
Univ Autonoma Estado Morelos, Fac Farm, 1001 Ave Univ, Cuernavaca 62209, Morelos, Mexico
Humberto Mojica-Vazquez, Luis:
Univ Nacl Autonoma Mexico, Genotoxicol Ambiental, Ctr Ciencias Atmosfera, Mexico City, DF, Mexico
Garcia-Carranca, Alejandro:
Univ Nacl Autonoma Mexico, Dept Biol Mol & Biotecnol, CDMX, Inst Invest Biomed, Mexico City 14080, DF, Mexico
Gonzalez-Maya, Leticia:
Univ Autonoma Estado Morelos, Fac Farm, 1001 Ave Univ, Cuernavaca 62209, Morelos, Mexico
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