Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

Abstract

Signal transducers and activators of transcription (STATs) are latent transcription factors that mediate cytokine-and growth factor-induced transcription. Constitutive activation of STAT3 has been shown in human cancers and transformed cell lines. We report that STAT3, but not STAT1 and STAT5, becomes phosphorylated in response to epidermal growth factor (EGF) and achieves maximal induction of collagenase-1 (MMP-1) transcription by interacting with c-JUN. Phosphorylation of STAT3 protein is biphasic: the first peak within 30 min and the second peak between 4 and 8 h. Association of STAT3 with c-JUN is detected and its constituting STAT3 is increasingly phosphorylated. The STAT and AP-1 elements are necessary for effective induction of MMP-1 promoter by EGF. Mutation of AP-1 element closely located at the STAT site abolishes the binding not only of c-JUN but also of STAT3 to MMP-1 promoter, resulting in the loss of the responsiveness to EGF. By blocking STAT3 activity with the dominant-negative form, we show the requirement of STAT3 for EGF induction of MMP-1 and MMP-10 (stromelysin-2). Furthermore, expression of the dominant-negative STAT3 is sufficient to inhibit the constitutive and EGF-inducible cell migration and invasion and the tumor formation in nude mice. These results demonstrate that STAT3 phosphorylation and its possible interaction with c-JUN are required for the strong responsiveness of MMP-1 to EGF, and STAT3 activation is crucial for exhibition of malignant characteristics in T24 bladder cancer cells.

A Significance of MMP-1 in EGFR-TKI Resistant Lung Adenocarcinoma: A Potential of Therapeutic Target

“…Results of global analyses using phosphorylation antibody array in our present study did reveal that EGFR pathway, especially mTOR related EGFR pathway was significantly associated with the induction of MMP-1 expression in PC9 cells and PC9/ER cells. These results were consistent with the previous report that EGFR pathway is important for the induction of MMP-1 expression in urinary bladder cancer [14], endometrial cancer [18], and others. The reason why EGFR-TKI resistant cells demonstrated significantly high expression of MMP-1 could be reasonably postulated as follows; in EGFR-TKI resistant lung adenocarcinoma cells, it is difficult to inhibit the increased EGFR pathway activity due to EGFR mutation.…”

“…However, the correlation between MMP-1 and EGFR-TKI resistant lung adenocarcinoma has not been studied. Itoh et al reported that signal transducers and activators of transcription 3 activity in response to EGF played pivotal roles in the process of MMP-1 induction in urinary bladder cancer [14]. In our present study, we therefore hypothesized that various activities of EGFR pathway associated with EGFR mutation and EGFR-TKI resistance could possibly change the expression levels of MMP-1 in EGFR-TKI resistant lung adenocarcinoma and contribute to the development of EGFR-TKI resistance.…”

“…Results of previously published studies demonstrated that the mechanisms of MMP-1 induction could possibly depend on each tumor [14,[16][17][18] , but those in lung carcinoma have virtually unknown. Results of global analyses using phosphorylation antibody array in our present study did reveal that EGFR pathway, especially mTOR related EGFR pathway was significantly associated with the induction of MMP-1 expression in PC9 cells and PC9/ER cells.…”

STAT3 is required but not sufficient for EGF receptor-mediated migration and invasion of human prostate carcinoma cell lines

“…Thus, the need for de novo transcription and translation that one notes during growth factor-induced motility (Kislauskis et al, 1997;Mingle et al, 2005), can be accomplished by a number of downstream transcription factors but requires STAT3 in addition to the previously determined PLCg pathway (Manos et al, 2001;Mamoune et al, 2004). Recently, it has been noted that EGFR signalling promotes progression of T24 bladder carcinoma cells via STAT3 upregulation of transcription, including that of matrix metaloproteinases (Itoh et al, 2006).…”

Mutations in JAK2V617F homologous domain of JAK genes are uncommon in solid tumors

“…Firstly, constitutive activation of the JAK2/Stat pathway, with potential role in oncogenesis, 8,9 occurs frequently in solid tumors, such as head and neck squamous cell carcinoma, 10 breast, 11,12 lung, 13 thyroid, 14 prostate 15 or bladder cancers. 16 Although overexpressed or mutated receptors, such as HER2 or EGF-R, have been implicated in some cases, the mechanisms of JAK/Stat activation in tumors remain mostly elusive. Secondly, anti-JAK inhibitors prevent cell growth from several tumor types.…”