Cytoplasmic p27 promotes epithelial–mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation

Abstract

p27 restrains normal cell growth, but PI3K-dependent C-terminal phosphorylation of p27 at threonine 157 (T157) and T198 promotes cancer cell invasion. Here, we describe an oncogenic feedforward loop in which p27pT157pT198 binds Janus kinase 2 (JAK2) promoting STAT3 (signal transducer and activator of transcription 3) recruitment and activation. STAT3 induces TWIST1 to drive a p27-dependent epithelial–mesenchymal transition (EMT) and further activates AKT contributing to acquisition and maintenance of metastatic potential. p27 knockdown in highly metastatic PI3K-activated cells reduces STAT3 binding to the TWIST1 promoter, TWIST1 promoter activity and TWIST1 expression, reverts EMT and impairs metastasis, whereas activated STAT3 rescues p27 knockdown. Cell cycle-defective phosphomimetic p27T157DT198D (p27CK-DD) activates STAT3 to induce a TWIST1-dependent EMT in human mammary epithelial cells and increases breast and bladder cancer invasion and metastasis. Data support a mechanism in which PI3K-deregulated p27 binds JAK2, to drive STAT3 activation and EMT through STAT3-mediated TWIST1 induction. Furthermore, STAT3, once activated, feeds forward to further activate AKT.

Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop

“…These results suggest that the CypB/STAT3/miR-520d-5p feedback loop is also present in clinical samples. Recently, researchers found that the transcription of TWIST1, a miR-520d-5p functional target (34), was increased by the activation of STAT3 and its binding to the TWIST1 promoter (47), suggesting another potential feedback loop that may regulate metastasis in gastric cancer.…”

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer

“…Tumor cell mesenchymalization takes place when epithelial cancer cells lose their polarity, cell-to-cell contacts, and expression of epithelial proteins, including E-cadherin, ZO-1, and cytokeratins, while gaining the expression of proteins normally found in mesenchymal cells, such as fibronectin and vimentin (34,35). Mesenchymalization and the molecular drivers of the process, including the transcription factors Snail, Slug, Twist, and brachyury, have been linked to advanced tumor stage (36)(37)(38), presence of metastases (39), and poor prognosis in numerous cancer types (40)(41)(42). Additionally, mesenchymalization has been associated with resistance to anticancer therapies, including chemotherapy (43,44), small-molecule-targeted therapies (45,46), and to lysis by immune effector cells (47)(48)(49)(50).…”

Musashi-2 promotes migration and invasion in bladder cancer via activation of the JAK2/STAT3 pathway

“…Jak2/STAT3 signaling has been shown to have a pivotal role in the epithelial-mesenchymal transition (EMT) to cancer cells, 16 and the importance of Jak2/STAT3 signaling in bladder cancer progression has been implicated. Zhao et al 27 showed that activation of Jak2/STAT3 in bladder cancer cells drove EMT and tumor invasion. Joung et al 28 reported that AG490, a Jak2 inhibitor, could inhibit bladder cancer cell viability and cell migration, accompanied by reduction of STAT3 signaling.…”