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.

Spinophilin acts as a tumor suppressor by regulating Rb phosphorylation

“…42 However, it is not clear how the loss of Spn might affect cellular behavior and contribute to tumorigenesis. In this study, we demonstrate that the loss of Spn affected the behavior of Rb through its ability to regulate the PPP1CA level and PP1a activity.…”

Spinophilin loss contributes to tumorigenesis in vivo

“…Proof-of-concept experiments overexpressing Spn shRNA in lung tumor cells showed increased tumorigenicity in the absence of p53. 18 In the work presented herein, we explore the contribution of the absence of SPN to tumorigenesis in vivo. To that end, we analyzed the effects of Spn loss in mouse models in detail.…”

Mutation of the nm23-H1 gene has a non-dominant role in colorectal adenocarcinoma

“…This region contains several putative tumor suppressor genes, including the Spn gene. Spn downregulation is associated with a poorer survival in patients with advanced stages of colorectal carcinoma (15), and downregulation of nm23-H1 contributes to tumorigenesis in lung cancer (16). Also, Qin et al (17) support the potential utility of targeting Nm23-H1 as a therapeutic approach for the treatment of Kaposi's sarcoma (17).…”