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.

BackgroundThere are few population-based studies of the sites of distant metastasis (DM) and survival from esophageal cancer (EC). The aim of this study was to assess the patterns and survival outcomes for site-specific DM from EC using a population-based approach.MethodsPatients diagnosed with de novo stage IV EC between 2010 and 2014 were identified from the Surveillance, Epidemiology, and End Results program database. Overall survival (OS) was compared according to the site of DM.ResultsWe included 3218 patients in this study; the most common site of DM was the liver, followed by distant lymph nodes, lung, bone and brain. Median OS for patients with liver, distant lymph node, lung, bone, and brain metastases was 5, 10, 6, 4, and 6 months, respectively (p<0.001). Site and number of distant metastases were independent prognostic factors for OS. In patients with a single site of DM, using liver metastases as reference, OS was lower for bone metastases (p=0.026) and higher for distant lymph node metastases (p=0.008), while brain (p=0.653) or lung (p=0.081) metastases had similar OS compared with liver metastases. Similar site-specific survival differences were observed in the subgroup with esophageal adenocarcinoma. However, distant lymph node metastases was associated with better survival (p=0.002) compared to liver, bone, or lung metastases in esophageal squamous cell carcinoma.ConclusionSite of metastasis affects survival in metastatic EC; OS was worst for bone metastases and greatest for distant lymph node metastases.

6-Phosphofructo 2-kinase/fructose 2, 6-bisphosphatase 3 (PFKFB3) has been reported to be overexpressed in human cancer tissues and to promote the proliferation and migration of cancer cells. However, the role of PFKFB3 in the progression and prognosis of breast cancer is not yet fully understood. In the present study, we investigated the specific role of PFKFB3 in breast cancer progression and its preliminary mechanisms of action. We first used an immunohistochemistry assay to determine that PFKFB3 was highly expressed in breast cancer tissues and that this high level of expression was involved in the poor overall survival of patients with breast cancer. In addition, the suppression of PFKFB3 by lentiviruses carrying shRNA against PFKFB3 (shPFKFB3) subsequently inhibited breast cancer cell (MDA-MB-231 and MDA-MB-468) proliferation, migration and invasion, and induced cell cycle G1 and S phase arrest in vitro. Moreover, PFKFB3 inhibition decreased p-AKT and increased p27 expression levels in breast cancer cells. Furthermore, PFKFB3 suppression inhibited breast cancer cell tumor xenograft growth in nude mice. We also found that PFKFB3 inhibition suppressed vascular endothelial growth factor α (VEGFα) protein expression and inhibited the angiogenic activity of human umbilical vein endothelial cells (HUVECs). On the whole, our results indicate that PFKFB3 is involved in the proliferation, migration, invasion and angiogenesis of breast cancer.

To determine the potential tumor suppressor functions of ubiquitin-specific protease 10 (USP10) in lung cancer and elucidate underlying molecular mechanism. The relative expression of USP10 was determined by real-time PCR and immunoblotting. The inhibitory effect of USP10 on tumor growth was demonstrated on allograft mice with Lewis carcinoma cell inoculation. The relative cell proliferation was measured with Cell Counting Kit-8 (CCK-8). The invasive capacity was evaluated by transwell assay. The interaction between USP10 and Phosphatase And Tensin Homolog (PTEN) was examined by co-immunoprecipitation. Ubiquitination/deubiquitination was analyzed by immunoprecipitation followed by immunoblotting. USP10 was down-regulated in lung cancer. Knockdown of USP10 promotes tumor growth and invasion both in vitro and in vivo. We further demonstrated that USP10 directly interacted with and stabilized PTEN via deubiquitination. The pro-cancerous effect of USP10 deficiency was abolished by re-introduction of PTEN. We suggested a tumor suppressor function of USP10 in lung cancer via deubiquitinating and stabilizing PTEN.