PKD1 Phosphorylation-Dependent Degradation of SNAIL by SCF-FBXO11 Regulates Epithelial-Mesenchymal Transition and Metastasis

SummaryMetastatic dissemination is often initiated by the reactivation of an embryonic development program referred to as epithelial-mesenchymal transition (EMT). The transcription factor SNAIL promotes EMT and elicits associated pathological characteristics such as invasion, metastasis, and stemness. To better understand the posttranslational regulation of SNAIL, we performed a luciferase-based, genome-wide E3 ligase siRNA library screen and identified SCF-FBXO11 as an important E3 that targets SNAIL for ubiquitylation and degradation. Furthermore, we discovered that SNAIL degradation by FBXO11 is dependent on Ser-11 phosphorylation of SNAIL by protein kinase D1 (PKD1). FBXO11 blocks SNAIL-induced EMT, tumor initiation, and metastasis in multiple breast cancer models. These findings establish the PKD1-FBXO11-SNAIL axis as a mechanism of posttranslational regulation of EMT and cancer metastasis

Stresses in the metastatic cascade: molecular mechanisms and therapeutic opportunities

Metastasis is the ultimate "survival of the fittest" test for cancer cells, as only a small fraction of disseminated tumor cells can overcome the numerous hurdles they encounter during the transition from the site of origin to a distinctly different distant organ in the face of immune and therapeutic attacks and various other stresses. During cancer progression, tumor cells develop a variety of mechanisms to cope with the stresses they encounter, and acquire the ability to form metastases. Restraining these stress-releasing pathways could serve as potentially effective strategies to prevent or reduce metastasis and improve the survival of cancer patients. Here, we provide an overview of the tumor-intrinsic, microenvironment- and treatment-induced stresses that tumor cells encounter in the metastatic cascade and the molecular pathways they develop to relieve these stresses. We also summarize the preclinical and clinical studies that evaluate the potential therapeutic benefit of targeting these stress-relieving pathways

Successful endoscopic combined with endovascular haemostasis of a ruptured pseudoaneurysm of the duodenal bulb: A case report

Pseudoaneurysms are uncommon but their rupture and bleeding can lead to serious complications and be fatal. We present here a case of a man in his late 70s who was transferred to our hospital with persistent gastrointestinal bleeding. One month prior to his admission, he had undergone surgery for a fracture to his left knee. Endoscopic examination found pulsating blood vessels on a duodenal ulcer, which suddenly ruptured and caused significant bleeding. Immediate endoscopic haemostasis was administered and the bleeding decreased. Considering the high rate of rebleeding that may occur with a pseudoaneurysm, the patient underwent interventional radiology that culminated in a diagnosis of a pseudoaneurysm originating from gastroduodenal artery (GDA); successful embolization was achieved. Tests showed that the patient had Helicobacter pylori infection. We hypothesised that the H. pylori infection had led to the occurrence of the duodenal bulb ulcer, and the patient’s left knee fracture and surgery a month previously had contributed to this predisposition for a pseudoaneurysm

Effects of an Oral Multi-vitamin Carbohydrate Beverage on Intraoperative Nausea and Vomiting in Women Converted from Vaginal Delivery to Cesarean Section

Background: Nausea and vomiting are common and unpleasant symptoms for pregnant women during cesarean section, which can lead to aspiration, a serious complication that can cause pneumonia. This study aimed to evaluate the effects of oral multi-vitamin carbohydrate beverage on maternal intraoperative nausea and vomiting by gastric ultrasound. Methods: This was a single-center, randomized controlled trial. According to their diet, pregnant women who were converted from vaginal delivery to cesarean section were divided into two groups: the observation group (multi-vitamin carbohydrate beverage) or the control group (semi-solid food). The cross-sectional area (CSA) of the gastric antrum was measured by ultrasound before cesarean section, and the occurrence of intraoperative nausea, vomiting, and aspiration was recorded in both groups. Results: The CSA of the gastric antrum at 1 h, 2 h, after eating, and before cesarean section in the observation group was significantly smaller than that in the control group. This suggests that an oral multi-vitamin carbohydrate beverage needs less gastric emptying time. The incidence of vomiting in the observation group was significantly lower than that in the control group. Moreover, the pH of the vomited fluid in the observation group was higher than that in the control group, indicating that oral multi-vitamin carbohydrate beverage may reduce the acidity of stomach contents, which can further reduce the risk and severity of vomiting. Conclusions: Oral multi-vitamin carbohydrate beverage can promote gastric emptying and reduce the incidence and harm of vomiting during urgent cesarean section. This dietary intervention may be a simple and effective way to improve maternal outcomes during cesarean section. Clinical Trial Registration: The study has been registered on https://classic.clinicaltrials.gov/ (registration number: NCT06333626)

Additional file 1 of Higher insoluble fiber intake is associated with a lower risk of prostate cancer: results from the PLCO cohort

Supplementary Material

Catalytic deactivation mechanism research over Cu/SAPO-34 catalysts for NH3-SCR (II): The impact of copper loading

Four Cu/SAPO-34 samples by one-pot method are utilized to examine their durability after 950 degrees C hydrothermal treatment and its relation with copper loading, The SCR results show fresh Cu/SAP0-34 with 3.91% copper loading (F-Cu-3.91) performs the superior NO conversion, wide temperature window and excellent nitrogen selectivity among fresh samples, and NO conversion is mainly determined by isolated Cu2+ contents at low temperature. After 950 degrees C aging treatment, Cu/SAPO-34 catalysts with copper loading under 1.70% present good stability, while the ones with copper loading above 3.91% show activity and crystallinity decline. Ex-situ DRIFTs, XRD and NH3-TPD results reveal the 950 degrees C aging process leads to Si-OH-Al bonds breakage and phase transition of chabazite support over Cu/SAPO-34 samples with high copper loading, meanwhile, the EPR and TPR outcomes prove the copper oxides' further dispersion and coordination variation due to skeleton collapse. Finally, this work is trying to manifest the appropriate copper loading for a stable Cu/SAPO-34 catalyst and its deactivation mechanism during extreme working situation. (C) 2017 Elsevier Ltd. All rights reserved

Supplemental Material, Fig_S1 - The Possible Role of Eukaryotic Translation Initiation Factor 3 Subunit e (eIF3e) in the Epithelial–Mesenchymal Transition in Adenomyosis

<p>Supplemental Material, Fig_S1 for The Possible Role of Eukaryotic Translation Initiation Factor 3 Subunit e (eIF3e) in the Epithelial–Mesenchymal Transition in Adenomyosis by Xianjun Cai, Minhong Shen, Xishi Liu, and Jichan Nie in Reproductive Sciences</p

Supplemental Material, Fig_S2 - The Possible Role of Eukaryotic Translation Initiation Factor 3 Subunit e (eIF3e) in the Epithelial–Mesenchymal Transition in Adenomyosis

<p>Supplemental Material, Fig_S2 for The Possible Role of Eukaryotic Translation Initiation Factor 3 Subunit e (eIF3e) in the Epithelial–Mesenchymal Transition in Adenomyosis by Xianjun Cai, Minhong Shen, Xishi Liu, and Jichan Nie in Reproductive Sciences</p

ASB13 inhibits breast cancer metastasis through promoting SNAI2 degradation and relieving its transcriptional repression of YAP

Transcription factor SNAI2 plays key roles during development and has also been known to promote metastasis by inducing invasive phenotype and tumor-initiating activity of cancer cells. However, the post-translational regulation of SNAI2 is less well studied. We performed a dual-luciferase-based, genome-wide E3 ligase siRNA library screen and identified ASB13 as an E3 ubiquitin ligase that targets SNAI2 for ubiquitination and degradation. ASB13 knockout in breast cancer cells promoted cell migration and decreased F-actin polymerization, while overexpression of ASB13 suppressed lung metastasis. Furthermore, ASB13 knockout decreased YAP expression, and such regulation is dependent on an increased protein level of SNAI2, which in turn represses YAP transcription. YAP suppresses tumor progression in breast cancer, as YAP knockout increases tumorsphere formation, anchorage-independent colony formation, cell migration in vitro, and lung metastasis in vivo. Clinical data analysis reveals that ASB13 expression is positively correlated with improved overall survival in breast cancer patients. These findings establish ASB13 as a suppressor of breast cancer metastasis by promoting degradation of SNAI2 and relieving its transcriptional repression of YAP

Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2

SNAI2/SLUG, a metastasis-promoting transcription factor, is a labile protein that is degraded through the ubiquitin proteasome degradation system. Here, we conducted comprehensive gain- and loss-of-function screens using a human DUB cDNA library of 65 genes and an siRNA library of 98 genes, and identified USP20 as a deubiquitinase (DUB) that regulates SNAI2 ubiquitination and stability. Further investigation of USP20 demonstrated its function in promoting migration, invasion, and metastasis of breast cancer. USP20 positively correlates with SNAI2 protein level in breast tumor samples, and higher USP20 expression is associated with poor prognosis in ER- breast cancer patients