Mecp2 fine-tunes quiescence exit by targeting nuclear receptors.

Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. A genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly disruption of two nuclear receptors, Rara or Nr1h3, accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.

Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma.

Chromothripsis is a catastrophic event of chromosomal instability that involves intensive fragmentation and rearrangements within localized chromosomal regions. However, its cause remains unclear. Here, we show that reduction and inactivation of Ran GTPase-activating protein 1 (RanGAP1) commonly occur in human osteosarcoma, which is associated with a high rate of chromothripsis. In rapidly expanding mouse osteoprogenitors, RanGAP1 deficiency causes chromothripsis in chr1q, instant inactivation of Rb1 and degradation of p53, consequent failure in DNA damage repair, and ultrafast osteosarcoma tumorigenesis. During mitosis, RanGAP1 anchors to the kinetochore, where it recruits PP1-γ to counteract the activity of the spindle-assembly checkpoint (SAC) and prevents TOP2A degradation, thus safeguarding chromatid decatenation. Loss of RanGAP1 causes SAC hyperactivation and chromatid decatenation failure. These findings demonstrate that RanGAP1 maintains mitotic chromosome integrity and that RanGAP1 loss drives tumorigenesis through its direct effects on SAC and decatenation and secondary effects on DNA damage surveillance.

Choice of operative method for pancreaticojejunostomy and a multivariable study of pancreatic leakage in pancreaticoduodenectomy.

BACKGROUND: As one of the major abdominal operations, pancreaticoduodenectomy (PD) involves many organs. The operation is complex, and the scope of the operation is large, which can cause significant trauma in patients. The operation has a high rate of complications. Pancreatic leakage is the main complication after PD. When pancreatic leakage occurs after PD, it can often lead to abdominal bleeding and infection, threatening the lives of patients. One study found that pancreatic leakage was affected by many factors including the choice of pancreaticojejunostomy method which can be well controlled. AIM: To investigate the choice of operative methods for pancreaticojejunostomy and to conduct a multivariate study of pancreatic leakage in PD. METHODS: A total of 420 patients undergoing PD in our hospital from January 2014 to March 2019 were enrolled and divided into group A (n = 198) and group B (n = 222) according to the pancreatointestinal anastomosis method adopted during the operation. Duct-to-mucosa pancreatojejunostomy was performed in group A and bundled pancreaticojejunostomy was performed in group B. The operation time, intraoperative blood loss, and pancreatic leakage of the two groups were assessed. The occurrence of pancreatic leakage after the operation in different patients was analyzed. RESULTS: The differences in operative time and intraoperative bleeding between groups A and B were not significant (P > 0.05). In group A, the time of pancreatojejunostomy was 26.03 ± 4.40 min and pancreatic duct diameter was 3.90 ± 1.10 mm. These measurements were significantly higher than those in group B (P < 0.05). The differences in the occurrence of pancreatic leakage, abdominal infection, abdominal hemorrhage and gastric retention between group A and group B were not significant (P > 0.05). The rates of pancreatic leakage in patients with preoperative albumin < 30 g/L, preoperative jaundice time ≥ 8 wk, and pancreatic duct diameter < 3 mm, were 23.33%, 33.96%, and 19.01%, respectively. These were significantly higher than those in patients with preoperative albumin ≥ 30 g/L, preoperative jaundice time < 8 wk, and pancreatic duct diameter ≥ 3 cm (P < 0.05). Logistic regression analysis showed that preoperative albumin < 30 g/L, preoperative jaundice time ≥ 8 wk, and pancreatic duct diameter < 3 mm were risk factors for pancreatic leakage after PD (odds ratio = 2.038, 2.416 and 2.670, P < 0.05). CONCLUSION: The pancreatointestinal anastomosis method during PD has no significant effect on the occurrence of pancreatic leakage. The main risk factors for pancreatic leakage include preoperative albumin, preoperative jaundice time, and pancreatic duct diameter.

Expression of caspase-3 and hypoxia inducible factor 1α in hepatocellular carcinoma complicated by hemorrhage and necrosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver. Its onset is latent, and it shows high heterogeneity and can readily experience intrahepatic metastasis or systemic metastasis, which seriously affects patients' quality of life. Numerous studies have shown that hypoxia inducible factor1α (HIF-1α) plays a significant role in the occurrence and development of tumors, as it promotes the formation of intratumoral vessels and plays a key role in their metastasis and invasion. Some studies have reported that caspase-3, which is induced by various factors, is involved in the apoptosis of tumor cells. AIM: To investigate the expression of caspase-3 and HIF-1α and their relationship to the prognosis of patients with primary HCC complicated by pathological changes of hemorrhage and necrosis. METHODS: A total of 88 patients with HCC complicated by pathological changes of hemorrhage and necrosis who were treated at our hospital from January 2017 to December 2019 were selected. The expression of caspase-3 and HIF-1α in HCC and paracancerous tissues from these patients was assessed. RESULTS: The positive expression rate of caspase-3 in HCC tissues was 27.27%, which was significantly lower than that in the paracancerous tissues (P < 0.05), while the positive expression rate of HIF-1α was 72.73%, which was significantly higher than that in the paracancerous tissues (P < 0.05). The positive expression rates for caspase-3 in tumor node metastasis (TNM) stage III and lymph node metastasis tissues were 2.78% and 2.50%, respectively, which were significantly lower than those in TNM stage I-II and non-lymph node metastasis tissues (P < 0.05). The positive expression rates of HIF-1α in TNM stage III, lymph node metastasis, and portal vein tumor thrombus tissues were 86.11%, 87.50%, and 88.00%, respectively, and these values were significantly higher than those in TNM stage I-II, non-lymph node metastasis, and portal vein tumor thrombus tissues (P < 0.05). The expression of caspase-3 and HIF-1α in HCC tissues were negatively correlated (r s = - 0.426, P < 0.05). The median overall survival time of HCC patients was 18.90 mo (95% CI: 17.20-19.91). The results of the Cox proportional risk regression model analysis showed that TNM stage, portal vein tumor thrombus, lymph node metastasis, caspase-3 expression, and HIF-1α expression were the factors influencing patient prognosis (P < 0.05). CONCLUSION: The expression of caspase-3 decreases and HIF-1α increases in HCC tissues complicated by pathological changes of hemorrhage and necrosis, and these are related to clinicopathological features and prognosis.

Vangl2 limits chaperone-mediated autophagy to balance osteogenic differentiation in mesenchymal stem cells.

Lysosomes are the recycling center and nutrient signaling hub of the cell. Here, we show that lysosomes also control mesenchymal stem cell (MSC) differentiation by proteomic reprogramming. The chaperone-mediated autophagy (CMA) lysosome subgroup promotes osteogenesis, while suppressing adipogenesis, by selectively removing osteogenesis-deterring factors, especially master transcriptional factors, such as adipogenic TLE3, ZNF423, and chondrogenic SOX9. The activity of the CMA-committed lysosomes in MSCs are controlled by Van-Gogh-like 2 (Vangl2) at lysosomes. Vangl2 directly binds to lysosome-associated membrane protein 2A (LAMP-2A) and targets it for degradation. MSC-specific Vangl2 ablation in mice increases LAMP-2A expression and CMA-lysosome numbers, promoting bone formation while reducing marrow fat. The Vangl2:LAMP-2A ratio in MSCs correlates inversely with the capacity of the cells for osteoblastic differentiation in humans and mice. These findings demonstrate a critical role for lysosomes in MSC lineage acquisition and establish Vangl2-LAMP-2A signaling as a critical control mechanism.