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Down‐regulation of spinophilin in lung tumours contributes to tumourigenesis
Author(s) -
MolinaPinelo Sonia,
Ferrer Irene,
BlancoAparicio Carmen,
Peregrino Sandra,
Pastor Maria Dolores,
AlvarezVega Juan,
Suarez Rocio,
Verge Mar,
Marin Juan J,
HernandezLosa Javier,
Cajal Santiago Ramon y,
PazAres Luis,
Carnero Amancio
Publication year - 2011
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2905
Subject(s) - lung , pathological , cancer research , phosphatase , small hairpin rna , lung cancer , knockout mouse , biology , cell growth , pathology , phosphorylation , medicine , receptor , apoptosis , microbiology and biotechnology , gene knockdown , biochemistry
The scaffold protein spinophilin (Spn, PPP1R9B) is one of the regulatory subunits of phosphatase‐1a (PP1), targeting it to distinct subcellular locations and to its target. Loss of Spn reduces PPP1CA levels, thereby maintaining higher levels of phosphorylated pRb. This effect contributes to an increase in p53 activity. However, in the absence of p53, reduced levels of Spn increase the tumourigenic properties of cells. In addition, Spn knockout mice have a reduced lifespan, an increased number of tumours and increased cellular proliferation in some tissues, such as the mammary ducts. In addition, the combined loss of Spn and p53 activity leads to an increase in mammary carcinomas, confirming the functional relationship between p53 and Spn. In this paper, we report that Spn is absent in 20% and reduced in another 37% of human lung tumours. Spn reduction correlates with malignant grade. Furthermore, the loss of Spn also correlates with p53 mutations. Analysis of miRNAs in a series of lung tumours showed that miRNA106a* targeting Spn is over‐expressed in some patients, correlating with decreased Spn levels. Proof‐of‐concept experiments over‐expressing miRNA106a* or Spn shRNA in lung tumour cells showed increased tumourigenicity. In conclusion, our data showed that miRNA106a* over‐expression found in lung tumours might contribute to tumourigenesis through Spn down‐regulation in the absence of p53. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.