The procedure outcome of laparoscopic resection for ′small′ hepatocellular carcinoma is comparable to vlaparoscopic radiofrequency ablation

Background: The aim of this study was to compare the effectiveness of laparoscopic liver resection (LLR) and laparoscopic radiofrequency ablation (LRFA) in the treatment of small nodular hepatocellular carcinoma (HCC). Patients and Methods: We enrolled 50 cirrhotic patients with similar baseline characteristics that underwent LLR (n = 26) or LRFA (n = 24), in both cases with intraoperative ultrasonography. Operative and peri-operative data were retrospectively evaluated. Results: LLR included anatomic resection in eight cases and non-anatomic resection in 18. In LRFA patients, a thermoablation of 62 nodules was achieved. Between LLR and LRFA groups, a significant difference was found both for median diameters of treated HCC nodules (30 vs. 17.1 mm; P < 0.001) and the number of treated nodules/patient (1.29 ± 0.62 vs. 2.65 ± 1.55; P < 0.001). A conversion to laparotomy occurred in two LLR patient (7.7%) for bleeding. No deaths occurred in both groups. Morbidity rates were 26.9% in the LLR group versus 16.6% in the LRFA group (P = 0.501). Hospital stay in the LLR and LRFA group was 8.30 ± 6.52 and 6.52 ± 2.69 days, respectively (P = 0.022). The surgical margin was free of tumour cells in all LLR patients, with a margin <5 mm in only one case. In the LRFA group, a complete response was achieved in 90.3% of thermoablated HCC nodules at the 1-month post-treatment computed tomography evaluation. Conclusions: LLR for small peripheral HCC in patients with chronic liver disease represents a valid alternative to LRFA in terms of patient toleration, surgical outcome of the procedure, and short-term morbidity

SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors

The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1\u3b1 (HIF-1\u3b1) and HIF-2\u3b1 (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity

USP15 is a deubiquitylating enzyme for receptor-activated SMADs.

The TGF\u3b2 pathway is critical for embryonic development and adult tissue homeostasis. On ligand stimulation, TGF\u3b2 and BMP receptors phosphorylate receptor-activated SMADs (R-SMADs), which then associate with SMAD4 to form a transcriptional complex that regulates gene expression through specific DNA recognition. Several ubiquitin ligases serve as inhibitors of R-SMADs, yet no deubiquitylating enzyme (DUB) for these molecules has so far been identified. This has left unexplored the possibility that ubiquitylation of R-SMADs is reversible and engaged in regulating SMAD function, in addition to degradation. Here we identify USP15 as a DUB for R-SMADs. USP15 is required for TGF\u3b2 and BMP responses in mammalian cells and Xenopus embryos. At the biochemical level, USP15 primarily opposes R-SMAD monoubiquitylation, which targets the DNA-binding domains of R-SMADs and prevents promoter recognition. As such, USP15 is critical for the occupancy of endogenous target promoters by the SMAD complex. These data identify an additional layer of control by which the ubiquitin system regulates TGF\u3b2 biology

Signaling crosstalk between TGFβ and Dishevelled/Par1b

Crosstalk of signaling pathways is critical during metazoan development and adult tissue homeostasis. Even though the transforming growth factor-beta (TGFβ) transduction cascade is rather simple, in vivo responsiveness to TGFβ ligands is tightly regulated at several steps. As such, TGFβ represents a paradigm for how the activity of one signaling system is modulated by others. Here, we report an unsuspected regulatory step involving Dishevelled (Dvl) and Par1b (also known as MARK2). Dvl and Par1b cooperate to enable TGFβ/bone morphogenetic protein (BMP) signaling in Xenopus mesoderm development and TGFβ responsiveness in mammalian cells. Mechanistically, the assembly of the Par1b/Dvl3/Smad4 complex is fostered by Wnt5a. The association of Smad4 to Dvl/Par1 prevents its inhibitory ubiquitination by ectodermin (also known as transcriptional intermediary factor 1 gamma or tripartite motif protein 33). We propose that this crosstalk is relevant to coordinate TGFβ responses with Wnt-noncanonical and polarity pathways

Role of Yap/Taz in mechanotransduction

Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment