Lysosomal cyst(e)ine storage potentiates tolerance to oxidative stress in cancer cells.

Cyst(e)ine is a key precursor for the synthesis of glutathione (GSH), which protects cancer cells from oxidative stress. Cyst(e)ine is stored in lysosomes, but its role in redox regulation is unclear. Here, we show that breast cancer cells upregulate major facilitator superfamily domain containing 12 (MFSD12) to increase lysosomal cyst(e)ine storage, which is released by cystinosin (CTNS) to maintain GSH levels and buffer oxidative stress. We find that mTORC1 regulates MFSD12 by directly phosphorylating residue T254, while mTORC1 inhibition enhances lysosome acidification that activates CTNS. This switch modulates lysosomal cyst(e)ine levels in response to oxidative stress, fine-tuning redox homeostasis to enhance cell fitness. MFSD12-T254A mutant inhibits MFSD12 function and suppresses tumor progression. Moreover, MFSD12 overexpression correlates with poor neoadjuvant chemotherapy response and prognosis in breast cancer patients. Our findings reveal the critical role of lysosomal cyst(e)ine storage in adaptive redox homeostasis and suggest that MFSD12 is a potential therapeutic target.

The phospholipid flippase ATP9A enhances macropinocytosis to promote nutrient starvation tolerance in hepatocellular carcinoma.

Macropinocytosis is an effective strategy to mitigate nutrient starvation. It can fuel cancer cell growth in nutrient-limited conditions. However, whether and how macropinocytosis contributes to the rapid proliferation of hepatocellular carcinoma cells, which frequently experience an inadequate nutrient supply, remains unclear. Here, we demonstrated that nutrient starvation strongly induced macropinocytosis in some hepatocellular carcinoma cells. It allowed the cells to acquire extracellular nutrients and supported their energy supply to maintain rapid proliferation. Furthermore, we found that the phospholipid flippase ATP9A was critical for regulating macropinocytosis in hepatocellular carcinoma cells and that high ATP9A levels predicted a poor outcome for patients with hepatocellular carcinoma. ATP9A interacted with ATP6V1A and facilitated its transport to the plasma membrane, which promoted plasma membrane cholesterol accumulation and drove RAC1-dependent macropinocytosis. Macropinocytosis inhibitors significantly suppressed the energy supply and proliferation of hepatocellular carcinoma cells characterised by high ATP9A expression under nutrient-limited conditions. These results have revealed a novel mechanism that overcomes nutrient starvation in hepatocellular carcinoma cells and have identified the key regulator of macropinocytosis in hepatocellular carcinoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Ambient Pressure Drying to Construct Cellulose Acetate/Benzoxazine Hybrid Aerogels with Flame Retardancy, Excellent Thermal Stability, and Superior Mechanical Strength Resistance to Cryogenic Temperature.

Cellulose aerogels are highly attractive candidates in various applications, such as thermal insulation, adsorption separation, biomedical field, and as carriers, due to their intrinsic merits of low density, high porosity, biodegradability, and renewability. However, the expensive cost of the supercritical drying process and poor mechanical properties limit their practical applications. Herein, a new method was presented to fabricate cellulose acetate/benzoxazine hybrid aerogels (CBAs) with low cost, low drying shrinkage, excellent mechanical properties under cryogenic condition (-196 °C), outstanding thermal insulation, flame retardancy, and good thermal stability by ambient pressure drying. In more detail, the weighted drying shrinkage rate of CBAs-T2 can be controlled to 6.8% (the average value along the radial and axial directions), mainly due to the enhanced skeleton, by introducing polybenzoxazine networking chains. The resultant CBAs-T2 exhibit outstanding mechanical properties at room temperature because of the presence of the polybenzoxazine hybrid in the cellulose networking system. CBAs-T2 still have good mechanical properties even after subjecting them to liquid nitrogen treatment. In addition, the optimal value of thermal conductivity (0.033 W m-1 K-1) is gained easily because of the uniform cross-linking networking structure and small pore size. A superior flame retardance of CBAs-T2 is endowed to achieve self-extinguishment after ignition, which is attributed to the presence of the aromatic ring in the backbone structure. Moreover, the good thermal stability of CBAs-T2 is attributed to the fact that polybenzoxazine components could resist the decomposition of cellulose acetate and inhibit heat release during the combustion process. Our study would provide a novel method for obtaining biomass aerogels including the cellulose-based materials system with low drying shrinkage and superior mechanical properties despite bearing a cryogenic environment by the low-cost ambient pressure drying approach.

Construction and Nanostructure of Chitosan/Nanocellulose Hybrid Aerogels.

Biomass aerogels have received extensive attention due to their unique natural characteristics. However, biomass-based chitosan aerogels are often confronted with the traditional issue concerning a weak skeleton structure, namely, the corresponding huge shrinkage for chitosan aerogels in the stage from the final gel to the aerogel. Herein, we put forward a new approach to enhance chitosan aerogels by introducing natural biomaterial cellulose nanocrystal (CNC). CNC is applied to connect/cross-link chitosan chains to form its networking construction through supramolecular interaction/physical entanglement, eventually realizing the enhancement of the chitosan aerogel network structure. Chitosan aerogels modified with CNC exhibit a high specific surface area of 578.43 cm2 g-1, and the pore size distribution is in the range of 20-60 nm, which is smaller than the mean free path of gas molecules (69 nm), triggering a "no convection" effect. Hence, the gaseous heat transfer of chitosan aerogel is effectively suppressed. Chitosan aerogels with the addition of CNC show an excellent thermal insulation property (0.0272 W m-1 K-1 at ambient condition) and an enhanced compressive strength (0.13 MPa at a strain of 3%). This improvement method of chitosan aerogel in enhancing the skeleton structure aspect provides a new kind of idea for strengthening the nanoscale morphology structure of biomass aerogels.

Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway.

Microtubule actin cross-linking factor 1 (Macf1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of Macf1 inhibited the differentiation of MC3T3-E1 cell line. However, whether Macf1 could regulate bone formation in vivo is unclear. To study the function and mechanism of Macf1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven Macf1 conditional knockout mice (Macf1f/f Osx-Cre). The Macf1f/f Osx-Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in Macf1f/f Osx-Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in Macf1f/f Osx-Cre mice. Deficiency of Macf1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of Macf1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of Macf1f/f Osx-Cre mice. Together, these results indicated that Macf1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that Macf1 might be a therapeutic target for bone disease.

MACF1, versatility in tissue-specific function and in human disease.

Spectraplakins are a family of evolutionarily conserved gigantic proteins and play critical roles in many cytoskeleton-related processes. Microtubule actin crosslinking factor 1 (MACF1) is one of the most versatile spectraplakin with multiple isoforms. As a broadly expressed mammalian spectraplakin, MACF1 is important in maintaining normal functions of many tissues. The loss-of-function studies using knockout mouse models reveal the pivotal roles of MACF1 in embryo development, skin integrity maintenance, neural development, bone formation, and colonic paracellular permeability. Mutation in the human MACF1 gene causes a novel myopathy genetic disease. In addition, abnormal expression of MACF1 is associated with schizophrenia, Parkinson's disease, cancer and osteoporosis. This demonstrates the crucial roles of MACF1 in physiology and pathology. Here, we review the research advances of MACF1's roles in specific tissue and in human diseases, providing the perspectives of MACF1 for future studies.

Incorporating a guanidine-modified cytosine base into triplex-forming PNAs for the recognition of a C-G pyrimidine-purine inversion site of an RNA duplex.

RNA duplex regions are often involved in tertiary interactions and protein binding and thus there is great potential in developing ligands that sequence-specifically bind to RNA duplexes. We have developed a convenient synthesis method for a modified peptide nucleic acid (PNA) monomer with a guanidine-modified 5-methyl cytosine base. We demonstrated by gel electrophoresis, fluorescence and thermal melting experiments that short PNAs incorporating the modified residue show high binding affinity and sequence specificity in the recognition of an RNA duplex containing an internal inverted Watson-Crick C-G base pair. Remarkably, the relatively short PNAs show no appreciable binding to DNA duplexes or single-stranded RNAs. The attached guanidine group stabilizes the base triple through hydrogen bonding with the G base in a C-G pair. Selective binding towards an RNA duplex over a single-stranded RNA can be rationalized by the fact that alkylation of the amine of a 5-methyl C base blocks the Watson-Crick edge. PNAs incorporating multiple guanidine-modified cytosine residues are able to enter HeLa cells without any transfection agent.

Platinum-Based Neoadjuvant Chemotherapy versus Primary Surgery in Ovarian Carcinoma International Federation of Gynecology and Obstetrics Stages IIIc and IV: A Systematic Review and Meta-Analysis.

BACKGROUND/AIM: This study aimed to compare neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) with primary debulking surgery (PDS) followed by chemotherapy in patients with advanced ovarian carcinoma International Federation of Gynecology and Obstetrics (FIGO) stages IIIc and IV. METHODS: PubMed, the Cochrane Library, and manual searches were applied to discriminate potentially eligible studies published before June 30, 2016. RESULTS: A total of 12 comparative studies were finally included; 1,372 patients underwent NAC followed by IDS, and 2,680 patients underwent PDS followed by chemotherapy. For overall pooled estimates, significant between-trial differences were found in the optimal debulking rate, grade 3-5 postoperative adverse reactions, and median overall survival (OS), but no difference was found in the median progression-free survival (PFS). Moreover, a significantly higher incidence was identified in major infections, vascular events, and wound complications for patients in the PDS group. CONCLUSIONS: This study suggested that NAC followed by IDS could improve the optimal debulking rate and decrease the postoperative adverse reactions for the current studies, but whether it could improve the OS and PFS compared with PDS followed by chemotherapy in patients with ovarian carcinoma FIGO stages IIIc and IV were still needed to be verified by conducting more randomized controlled trials.

Research progress on polybenzoxazine aerogels: Preparation, properties, composites and hybrids fabrication, applications.

The unremitting pursuit of high-performance and multifunctional materials has consistently propelled modern industries forward, stimulating research and motivating progress in related fields. In such materials, polybenzoxazine (PBz) aerogel, which combines the virtues of PBz and aerogel, has attracted salient attention recently, emerging as a novel research focus in the realm of advanced materials. In this review, the preparation scheme, microscopic morphology, and fundamental characteristics of PBz aerogels are comprehensively summarized and discussed in anticipation of providing a clear understanding of the correlation between preparation process, structure, and properties. The effective strategies for enhancing the performance of PBz aerogels including composite fabrication and hybridization are highlighted. Moreover, the applications of PBz-based aerogels in various domains such as adsorption (including wastewater treatment, CO2 capture, and microwave adsorption), thermal insulation, energy storage as well as sensors are covered in detail. Furthermore, several obstacles and potential directions for subsequent research are delineated with a view to surmounting the prevailing constraints and achieving a realization of the shift from experimental exploration to practical applications.

A novel immune-related gene signature for diagnosis and potential immunotherapy of microsatellite stable endometrial carcinoma.

An immune-related gene signature (IRGS) was established to better understand the molecular and immunologic characteristics of microsatellite instable (MSI) and microsatellite stable (MSS) endometrial carcinoma (EC), and provide potential immunotherapy directions for MSS patients. Top 20 immune-related hub genes were screened by weight gene coexpression network analysis (WGCNA), and an IRGS was further established through Cox regression analysis. The molecular and immune characteristics were clarified in IRGS high and low risk groups. Expression and MS status validation of the IRGS were conducted through quantitative real-time Polymerase Chain Reaction (rt-qPCR) and immunohistochemistry (IHC) analysis. The IRGS includes 2 oncogenes (AGTR1 and HTR3C) and 2 tumor suppressor genes (CD3E and SERPIND1). Patients in IRGS high-risk group were more with MSS status, higher tumor grade, later FIGO stage, serous histology and elder ages compared with IRGS low-risk group (P < 0.05). Besides, patients in MSS group were more FIGO stages II-IV (42.7% vs. 26%), serous histology (35.7% vs. 5.3%) and with higher IRGS risk score (1.51 ± 3.11 vs. 1.02 ± 0.67) (P < 0.05) than patients in MSI group. Furthermore, patients in IRGS high-risk group had higher tumor purity, more Macrophages M1 and Macrophages M2 infiltrating, higher proportion of Macrophages M2 and Dendritic cells activated, lower proportion of T cells regulatory (Tregs), lower tumor mutation burden (TMB). Correspondingly, subjects in IRGS low-risk group had higher immunphenoscores than IRGS high-risk group. The relative mRNA level of AGTR1 and HTR3C were gradually increase, while CD3E and SERPIND1 were reversed in rt-qPCR. Through IHC experiments, AGTR1(69.2% vs 30%, P = 0.074) and HTR3C (76.9% vs 30%, P = 0.024) had higher positive staining rates in ECs than non-ECs. While SERPIND1 (84.6% vs 20%, P = 0.003) and CD3E (61.5% vs 40%, P = 0.000) had higher positive staining rates in non-ECs. IRGS is a potential diagnostic and prognostic biomarker for EC. IRGS low risk group might benefit from immune checkpoint inhibitors, while IRGS high risk group deserve other potential immunotherapy.

Chitosan/silica hybrid aerogels with synergistic capability for superior hydrophobicity and mechanical robustness.

Chitosan aerogels could be applied potentially in thermal insulation for energy-saving buildings, separation/adsorption, and catalysis. However, disadvantages of chitosan aerogels include their hydrophilicity and low insufficient mechanical strength. Here we propose a silica-phase hybriding route to create chitosan/silica hybrid aerogels with a synergistic capability for favourable hydrophobicity and superior mechanical strength, demonstrating an emergent finding (hydrophobicity optimised with the improved mechanical strength). The aerogels exhibit low drying shrinkage (as low as 13.41 %), lightweight (lowest to 0.149 g cm-1), high-efficient thermal insulation (thermal conductivity as low as to 0.024 W m-1 K-1 at room temperature and normal pressure) either under cryogenic (-196 °C) or high-temperature conditions, exceptional fire-retardancy (self-extinguishing in 1.8 s) and environmentally friendly characteristic (initial mineralisation after 10 d). High hydrophobic property (water contact angle up to 142°) of the aerogels were achieved depending upon 1H, 1H, 2H, 2H-perfluorodecyltriethoxysilane of vapor deposition, presenting a discovery concerning substantial improvement of mechanical properties (up to 0.188 MPa at 5 % strain, increased by 25 %). Furthermore, we demonstrate that a plausible mechanism for simultaneous hydrophobic and mechanical enhancement is depending upon the modulation of networking skeletons at the nanoscale.

Inhibition of DPAGT1 suppresses HER2 shedding and trastuzumab resistance in human breast cancer.

Human epidermal growth factor receptor 2-targeted (HER2-targeted) therapy is the mainstay of treatment for HER2+ breast cancer. However, the proteolytic cleavage of HER2, or HER2 shedding, induces the release of the target epitope at the ectodomain (ECD) and the generation of a constitutively active intracellular fragment (p95HER2), impeding the effectiveness of anti-HER2 therapy. Therefore, identifying key regulators in HER2 shedding might provide promising targetable vulnerabilities against resistance. In the current study, we found that upregulation of dolichyl-phosphate N-acetylglucosaminyltransferase (DPAGT1) sustained high-level HER2 shedding to confer trastuzumab resistance, which was associated with poor clinical outcomes. Upon trastuzumab treatment, the membrane-bound DPAGT1 protein was endocytosed via the caveolae pathway and retrogradely transported to the ER, where DPAGT1 induced N-glycosylation of the sheddase - ADAM metallopeptidase domain 10 (ADAM10) - to ensure its expression, maturation, and activation. N-glycosylation of ADAM10 at N267 protected itself from ER-associated protein degradation and was essential for DPAGT1-mediated HER2 shedding and trastuzumab resistance. Importantly, inhibition of DPAGT1 with tunicamycin acted synergistically with trastuzumab treatment to block HER2 signaling and reverse resistance. These findings reveal a prominent mechanism for HER2 shedding and suggest that targeting DPAGT1 might be a promising strategy against trastuzumab-resistant breast cancer.

BAG2 drives chemoresistance of breast cancer by exacerbating mutant p53 aggregate.

Rationale: Chemoresistance is a major challenge in the clinical management of patients with breast cancer. Mutant p53 proteins tend to form aggregates that promote tumorigenesis in cancers. We here aimed to explore the mechanism for the generation of mutant p53 aggregates in breast cancer and assess its role in inducing chemoresistance. Methods: Expression of BCL2-associated athanogene 2 (BAG2) was evaluated by qRT-PCR, western blotting, and immunohistochemistry in breast cancer patient specimens. The significance of BAG2 expression in prognosis was assessed by Kaplan-Meier survival analysis and the Cox regression model. The roles of BAG2 in facilitating the formation of mutant p53 aggregates were analyzed by co-immunoprecipitation, immunofluorescence, and semi-denaturing detergent-agarose gel electrophoresis assays. The effects of BAG2 on the chemoresistance of breast cancer were demonstrated by cell function assays and mice tumor models. Results: In the present study, we found that BAG2 was significantly upregulated in relapse breast cancer patient tissues and high BAG2 was associated with a worse prognosis. BAG2 localized in mutant p53 aggregates and interacted with misfolded p53 mutants. BAG2 exacerbated the formation of the aggregates and recruited HSP90 to promote the propagation and maintenance of the aggregates. Consequently, BAG2-mediated mutant p53 aggregation inhibited the mitochondrial apoptosis pathway, leading to chemoresistance in breast cancer. Importantly, silencing of BAG2 or pharmacological targeting of HSP90 substantially reduced the aggregates and increased the sensitivity of chemotherapy in breast cancer. Conclusion: These findings reveal a significant role of BAG2 in the chemoresistance of breast cancer via exacerbating mutant p53 aggregates and suggest that BAG2 may serve as a potential therapeutic target for breast cancer patients with drug resistance.

Long noncoding RNA LINC00173 induces radioresistance in nasopharyngeal carcinoma via inhibiting CHK2/P53 pathway.

Radiotherapy is the backbone of nasopharyngeal carcinoma (NPC), nearly 11-17% NPC patients suffered local relapse and 18-37% suffered distant metastasis mainly due to radioresistance. Therefore, the key of improving patients' survivals is to investigate the mechanism of radioresistance. In this study, we revealed that the expression level of long intergenic nonprotein coding RNA 173 (LINC00173) was significantly increased in the radioresistant NPC patients' tumour tissues compared with the radiosensitive patients by RNA-sequencing, which also predict poor prognosis in NPC. Overexpression of LINC00173 induced radioresistance of NPC cells in vitro and in vivo. Mechanistically, LINC00173 bound with checkpoint kinase 2 (CHK2) in nucleus, and impaired the irradiation-induced CHK2 phosphorylation, then suppressed the activation of P53 signalling pathway, which eventually inhibiting apoptosis and leading to radioresistance in NPC cells. In summary, LINC00173 decreases the occurrence of apoptosis through inhibiting the CHK2/P53 pathway, leads to NPC radioresistance and could be considered as a novel predictor and therapeutic target in NPC.

A Wnt-induced lncRNA-DGCR5 splicing switch drives tumor-promoting inflammation in esophageal squamous cell carcinoma.

Alternative splicing (AS) is a critical mechanism for the aberrant biogenesis of long non-coding RNA (lncRNA). Although the role of Wnt signaling in AS has been implicated, it remains unclear how it mediates lncRNA splicing during cancer progression. Herein, we identify that Wnt3a induces a splicing switch of lncRNA-DGCR5 to generate a short variant (DGCR5-S) that correlates with poor prognosis in esophageal squamous cell carcinoma (ESCC). Upon Wnt3a stimulation, active nuclear ß-catenin acts as a co-factor of FUS to facilitate the spliceosome assembly and the generation of DGCR5-S. DGCR5-S inhibits TTP's anti-inflammatory activity by protecting it from PP2A-mediated dephosphorylation, thus fostering tumor-promoting inflammation. Importantly, synthetic splice-switching oligonucleotides (SSOs) disrupt the splicing switch of DGCR5 and potently suppress ESCC tumor growth. These findings uncover the mechanism for Wnt signaling in lncRNA splicing and suggest that the DGCR5 splicing switch may be a targetable vulnerability in ESCC.

The effect of cold-knife conization on pregnancy outcomes in patients with cervical lesions.

OBJECTIVE: To analyze the pregnancy outcomes of patients with cervical lesions treated by cold-knife conization (CKC). METHODS: Clinical data of healthy pregnant women and pregnant women who underwent CKC in Dalian Women and Children's Medical Group from March 2010 to December 2019 were retrospectively analyzed. These patients were divided into a CKC group and a control group according to inclusion and exclusion criteria. Statistical methods were used to compare pregnancy and delivery outcomes between the two groups. RESULTS: There were 400 patients in CKC group and control group, with 200 patients in each. There was no significant difference in the mode of delivery, abortion, ectopic pregnancy, in-hospital perinatal management, and cervical cerclage between the CKC group and the control group (P>0.05). The rates of preterm delivery, premature rupture of membranes, cesarean section, and neonatal admission in the CKC group were higher than those in the control group (P<0.05). In the CKC group, the incidence of premature rupture of membranes within six months postoperatively was higher than that after six months (P<0.05). The incidences of preterm delivery and premature rupture of membranes were not completely consistent in different conization ranges (P<0.05). CONCLUSION: CKC increases the incidence of preterm delivery, premature rupture of membranes, and neonatal adverse outcomes. Conization height can predict the occurrence of preterm delivery. Delaying pregnancy after surgery can reduce the incidence of adverse outcomes during the perinatal period.

Chitosan Based Aerogels with Low Shrinkage by Chemical Cross-Linking and Supramolecular Interaction.

Chitosan (CTS) aerogel is a new type of functional material that could be possibly applied in the thermal insulation field, especially in energy-saving buildings. However, the inhibition method for the very big shrinkage of CTS aerogels from the final gel to the aerogel is challenging, causing great difficulty in achieving a near-net shape of CTS aerogels. Here, this study explored a facile strategy for restraining CTS-based aerogels' inherent shrinkage depending on the chemical crosslinking and the interpenetrated supramolecular interaction by introducing nanofibrillar cellulose (NFC) and polyvinyl alcohol (PVA) chains. The effects of different aspect ratios of NFC on the CTS-based aerogels were systematically analyzed. The results showed that the optimal aspect ratio for NFC introduction was 37.5 from the comprehensive property perspective. CTS/PVA/NFC hybrid aerogels with the aspect ratio of 37.5 for NFC gained a superior thermal conductivity of 0.0224 W/m K at ambient atmosphere (the cold surface temperature was only 33.46 °C, despite contacting the hot surface of 80.46 °C), a low density of 0.09 g/cm3, and a relatively high compressive stress of 0.51 MPa at 10% strain.

Hydrophobic Cellulose Acetate Aerogels for Thermal Insulation.

As naturally derived material, cellulose aerogels have excellent thermal insulation properties due to their unique high porosity and three-dimensional mesoporous structure. However, its hydrophilic properties limit its application in the field of building insulation. Here, we propose a method to prepare high hydrophobicity by adopting the sol-gel method and chemical vapor reaction strategy using cellulose acetate type II as raw material and 2,4-toluene diisocyanate as the cross-linking agent. Thermal properties of cellulose acetate aerogels (CAAs) were measured, where pyridine was the catalyst, acetone was the solvent, and perfluorodecyltriethoxysilane (PFDS), hexamethyldisilazane (HMDS), and methyltriethoxysilane (MTES) were used as hydrophobic agents (by process hydrophobic test). Compared with MTES-modified cellulose acetate aerogels (M-CAAs) and HMDS (H-CAAs)-modified cellulose acetate aerogels, PFDS-modified (P-CAAs) cellulose acetate aerogels are the most hydrophobic. By implementing hydrophobic modification of PFDS both inside and outside the structure of cellulose acetate aerogels, the water contact angle can reach up to 136°, strongly demonstrating the potential of PFDS as a hydrophobic agent. The results show that the thermal conductivity and compressive strength of cellulose acetate aerogel with the best hydrophobic properties are 0.035 W m-1 K-1 at normal pressure and 0.39 MPa at 3% strain, respectively. This work shows that the highly hydrophobic cellulose acetate aerogel has potential as a waterproof material in the field of building thermal-insulation materials.

MEX3C-Mediated Decay of SOCS3 mRNA Promotes JAK2/STAT3 Signaling to Facilitate Metastasis in Hepatocellular Carcinoma.

Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)-mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3'UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC. SIGNIFICANCE: This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple-negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta.

Triple-negative breast cancer (TNBC) is fast-growing and highly metastatic with the poorest prognosis among the breast cancer subtypes. Inactivation of glycogen synthase kinase 3 beta (GSK3ß) plays a vital role in the aggressiveness of TNBC; however, the underlying mechanism for sustained GSK3ß inhibition remains largely unknown. Here, we find that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) is upregulated in TNBC and relevant to poor prognosis in patients. Overexpression of PPP1R14C facilitates cell proliferation and the aggressive phenotype of TNBC cells, whereas the depletion of PPP1R14C elicits opposite effects. Moreover, PPP1R14C is phosphorylated and activated by protein kinase C iota (PRKCI) at Thr73. p-PPP1R14C then represses Ser/Thr protein phosphatase type 1 (PP1) to retain GSK3ß phosphorylation at high levels. Furthermore, p-PPP1R14C recruits E3 ligase, TRIM25, toward the ubiquitylation and degradation of non-phosphorylated GSK3ß. Importantly, the blockade of PPP1R14C phosphorylation inhibits xenograft tumorigenesis and lung metastasis of TNBC cells. These findings provide a novel mechanism for sustained GSK3ß inactivation in TNBC and suggest that PPP1R14C might be a potential therapeutic target.