RESUMO
Colon cancer is a prevalent malignancy, while recent studies revealed the dys-regulation of Hippo signaling as the important driver for colon cancer progression. Several studies have indicated that post-translational modifications on YAP play crucial roles in both Hippo signaling activity and cancer progression. This raises a puzzling question about why YAP/TAZ, an auto-inhibitory pathway, is frequently over-activated in colon cancer, despite the suppressive cascade of Hippo signaling remaining operational. The protein stability of YAP is subject to a tiny balance between ubiquitination and deubiquitination processes. Through correlation analysis of DUBs (deubiquitinases) expression and Hippo target gene signature in colon cancer samples, we found JOSD1 as a critical deubiquitinase for Hippo signaling and colon cancer progression. JOSD1 could facilitate colon cancer progression and in colon cancer, inhibition of JOSD1 via shRNA has been demonstrated to impede tumorigenesis. Furthermore, molecular mechanism studies have elucidated that JOSD1 enhances the formation of the Hippo/YAP transcriptome by impeding K48-linked polyubiquitination on YAP. ChIP assays have shown that YAP binds to JOSD1's promoter region, promoting its gene transcription. These results suggest that JOSD1 is involved in both activating and being targeted by the Hippo signaling pathway in colon cancer. Consequently, a positive regulatory loop between JOSD1 and Hippo signaling has been identified, underscoring their interdependence during colon cancer progression. Thus, targeting JOSD1 may represent a promising therapeutic approach for managing colon cancer.
RESUMO
BACKGROUND: Pancreaticojejunostomy, an independent risk factor for pancreatic fistula, is the cause of several postoperative complications of pancreaticoduodenectomy. As suturing in minimally invasive surgery is difficult to perform, more simplified methods are needed to guarantee a safe pancreatic anastomosis. The concept of "biological healing" proposed in recent years has changed the conventional understanding of the anastomosis, which recommends rich blood supply, low tension, and loose sutures in the reconstruction of the pancreatic outflow tract. METHODS: A literature search was conducted in PubMed for articles on pancreaticojejunostomy published between January 2014 and December 2021. After following a due selection process, several techniques developed in accordance with the concept of biological healing that were found suitable for minimally invasive surgery and their related clinical outcomes were described in this review. RESULTS: The incidence of clinically relevant pancreatic fistula associated with the presented techniques did not exceed 15.9%, indicating superior results compared to Cattell-Warren double-layer duct-to-mucosa anastomosis (incidence: approximately 20%). The features and drawbacks of these approaches have been enumerated from the viewpoint of biological healing. CONCLUSIONS: This review described several modified pancreaticojejunostomy techniques with the advantages of a simplified procedure and a lower incidence of pancreatic fistula. Surgeons can choose to apply them in clinical practice to improve patient prognosis.