Open AccessCritical roles of the c AMP ‐responsive element‐binding protein‐mediated pathway in disorganized epithelial phenotypes caused by mitochondrial dysfunction
Author(s) -
Shibanuma Motoko,
Ishikawa Fumihiro,
Kobayashi Masayuki,
Katayama Kazufumi,
Miyoshi Hiroyuki,
Wakamatsu Masami,
Mori Kazunori,
Nose Kiyoshi
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2012.02369.x
Subject(s) - creb , biology , microbiology and biotechnology , hmga2 , gene knockdown , cancer research , transcription factor , apoptosis , microrna , genetics , gene
In most human cancers, somatic mutations have been identified in the mt DNA ; however, their significance remains unclear. We recently discovered that NM u MG mouse mammary epithelial cells, when deprived of mitochondria or following inhibition of respiratory activity, undergo epithelial morphological disruption accompanied with irregular edging of E ‐cadherin, the appearance of actin stress fibers, and an altered gene expression profile. In this study, using the mt DNA ‐less pseudo ρ0 cells obtained from NM u MG mouse mammary epithelial cells, we examined the roles of two mitochondrial stress‐associated transcription factors, c AMP ‐responsive element‐binding protein ( CREB ) and C / EBP homologous protein‐10 ( CHOP ), in the disorganization of epithelial phenotypes. We found that the expression of matrix metalloproteinase‐13 and that of GADD 45 A , SNAIL and integrin α1 in the ρ0 cells were regulated by CHOP and CREB , respectively. Of note, knockdown and pharmacological inhibition of CREB ameliorated the disrupted epithelial morphology. It is interesting to note that the expression of high mobility group AT ‐hook 2 ( HMGA 2), a non‐histone chromatin protein implicated in malignant neoplasms, was increased at the protein level through the CREB pathway. Here, we reveal how the activation of the CREB / HMGA 2 pathway is implicated in the repression of integrin α1 expression in H ep G 2 human cancer cells, highlighting the importance of the CREB / HMGA 2 pathway in malignant transformation associated with mitochondrial dysfunction, thereby raising the possibility that the pathway indirectly interferes with the cell–cell adhesion structure by influencing the cell–extracellular matrix adhesion status. Overall, the data suggest that mitochondrial dysfunction potentially contributes to neoplastic transformation of epithelial cells through the activation of these transcriptional pathways.