Doubles Game: Src-Stat3 versus p53-PTEN in Cellular Migration and Invasion

Abstract

We have recently shown that Src induces the formation of podosomes and cell invasion by suppressing endogenous p53, while enhanced p53 strongly represses the Src-induced invasive phenotype. However, the mechanism by which Src and p53 play antagonistic roles in cell invasion is unknown. Here we show that the Stat3 oncogene is a required downstream effector of Src in inducing podosome structures and related invasive phenotypes. Stat3 promotes Src phenotypes through the suppression of p53 and the p53-inducible protein caldesmon, a known podosome antagonist. In contrast, enhanced p53 attenuates Stat3 function and Srcinduced podosome formation by upregulating the tumor suppressor PTEN. PTEN, through the inactivation of Src/Stat3 function, also stabilizes the podosome-antagonizing p53/caldesmon axis, thereby further enhancing the anti-invasive potential of the cell. Furthermore, the protein phosphatase activity of PTEN plays a major role in the negative regulation of the Src/Stat3 pathway and represses podosome formation. Our data suggest that cellular invasiveness is dependent on the balance between two opposing forces: the proinvasive oncogenes Src-Stat3 and the anti-invasive tumor suppressors p53-PTEN.p53 is a potent tumor suppressor that plays a critical role in the regulation of cell cycle progression, DNA repair, apoptosis, and senescence (3,10,32,57). Approximately half of all human tumors have compromised p53 function (25, 62). Loss of p53 function has also been implicated in the evolution of aggressive and metastatic cancers (28,33,42,43), suggesting an antiinvasive and migration role of p53. Recent studies have increasingly unveiled this relatively less known aspect of p53 function in the regulation of cell migration and invasion (19,20,45,63,66). We have recently shown that p53, acting downstream of Src, strongly suppresses the formation of podosomes (also called invadopodia in cancer cells) and extracellular matrix (ECM) digestion by upregulating the expression of caldesmon, a known antagonist of podosomes (44).Src, a proto-oncogenic nonreceptor tyrosine kinase, induces migratory and invasive phenotypes in various cell types by initiating extensive cytoskeletal rearrangements (38,51,67). Activated Src induces the formation of podosomes and rosettes of podosomes, which are dynamic, actin-rich membrane protrusions (9,24,40), specialized in the degradation of the ECM by the recruitment and secretion of matrix metalloproteinases (MMPs) (8,38,60,64

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

“…We also observed a minor downregulation of STAT3 expression in TP53 +/+ cells. A similar observation was reported previously (31). When miR34a was specifically inhibited by an antagomir, the repression of IL-6R and STAT3 as well as the p53-mediated decrease in STAT3 phosphorylation was prevented ( Figure 4F and Supplemental Figure 5C), demonstrating that miR-34a mediates these effects of p53.…”

The overexpression of SOX2 affects the migration of human teratocarcinoma cell line NT2/D1

“…Recent studies suggest that the effects of p53 on the processes of migration and invasion are cell context-dependent (Hollstein et al 1991, Vogelstein et al 2000, Lewis et al 2005, Moskovits et al 2006, Ku et al 2007, Morton et al 2008, Mukhopadhyay et al 2010. In line with our results, the accumulation of p53 protein in mouse embryonic fibroblasts has been revealed in the condition of forced expression of SOX2 (Li et al 2009, Banito andGil 2010).…”

Microrna-136 promotes proliferation and invasion ingastric cancer cells through Pten/Akt/P-Akt signaling pathway

“…It has been well established that PTEN may serve functions in a number of biological processes, including cell proliferation, the cell cycle, apoptosis, migration, invasion, metastasis, metabolism, differentiation, transcription and translation through negative regulation of the PI3K/AKT signaling pathway (38)(39)(40)(41)(42). Li et al (24) reported that in gastric cancer, PTEN expression is low in tumor tissues and was associated with advanced clinical stage and poor prognosis of patients with gastric cancer.…”