Down-regulation of spinophilin in lung tumours contributes to tumourigenesis

Abstract

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.