FAT10 mediates the sorafenib-resistance of hepatocellular carcinoma cells by stabilizing E3 ligase NEDD4 to enhance PTEN/AKT pathway-induced autophagy.

Although sorafenib is the first-line therapeutic agent for advanced hepatocellular carcinoma (HCC), the development of drug resistance in HCC cells limits its clinical efficacy. However, the key factors involved in mediating the sorafenib resistance of HCC cells and the underlying mechanisms have not been elucidated. In this study, we generated sorafenib-resistant HCC cell lines, and our data demonstrate that HLA-F locus-adjacent transcript 10 (FAT10), a ubiquitin-like protein, is markedly upregulated in sorafenib-resistant HCC cells and that reducing the expression of FAT10 in sorafenib-resistant HCC cells increases sensitivity to sorafenib. Mechanistically, FAT10 stabilizes the expression of the PTEN-specific E3 ubiquitin ligase NEDD4 that causes downregulation of PTEN, thereby inducing AKT-mediated autophagy and promoting the resistance of HCC cells to sorafenib. Moreover, we screened the small molecule Compound 7695-0983, which increases the sensitivity of sorafenib-resistant HCC cells to sorafenib by inhibiting the expression of FAT10 to inhibit NEDD4-PTEN/AKT axis-mediated autophagy. Collectively, our preclinical findings identify FAT10 as a key factor in the sorafenib resistance of HCC cells and elucidate its underlying mechanism. This study provides new mechanistic insight for the exploitation of novel sorafenib-based tyrosine kinase inhibitor (TKI)-targeted drugs for treating advanced HCC.

Ba6RE2Ti4O17 (RE = Nd, Sm, Gd, Dy-Yb): A Family of Rare-Earth-Based Layered Triangular Lattice Magnets.

The exploration of new rare-earth (RE)-based triangular-lattice materials plays a significant role in motivating the discovery of exotic magnetic states. Herein, we report a family of hexagonal perovskite compounds Ba6RE2Ti4O17 (RE = Nd, Sm, Gd, Dy-Yb) with a space group of P63/mmc, where magnetic RE3+ ions are distributed on the parallel triangular-lattice layers within the ab-plane and stacked in an 'AA'-type fashion along the c-axis. The low-temperature magnetic characterizations indicate that all synthesized Ba6RE2Ti4O17 compounds exhibit dominant antiferromagnetic (AFM) interactions and the absence of magnetic order down to 1.8 K. The isothermal magnetization and electron spin resonance results reveal the distinct magnetic anisotropy for the compounds with different RE ions. Moreover, the as-grown Ba6Nd2Ti4O17 single crystals exhibit Ising-like magnetic anisotropy with a magnetic easy-axis perpendicular to the triangle-lattice plane and no long-range magnetic order down to 80 mK, as the quantum spin liquid candidate with dominant Ising-type interactions.

Construction of Ideal One-Dimensional Spin Chains by Topochemical Dehydration/Rehydration Route.

One-dimensional (1D) Heisenberg antiferromagnets are of great interest due to their intriguing quantum phenomena. However, the experimental realization of such systems with large spin S remains challenging because even weak interchain interactions induce long-range ordering. In this study, we present an ideal 1D S = 5/2 spin chain antiferromagnet achieved through a multistep topochemical route involving dehydration and rehydration. By desorbing three water molecules from (2,2'-bpy)FeF3(H2O)·2H2O (2,2'-bpy = 2,2'-bipyridyl) at 150 °C and then intercalating two water molecules at room temperature (giving (2,2'-bpy)FeF3·2H2O 1), the initially isolated FeF3ON2 octahedra combine to form corner-sharing FeF4N2 octahedral chains, which are effectively separated by organic and added water molecules. Mössbauer spectroscopy reveals significant dynamical fluctuations down to 2.7 K, despite the presence of strong intrachain interactions. Moreover, results from electron spin resonance (ESR) and heat capacity measurements indicate the absence of long-range order down to 0.5 K. This controlled topochemical dehydration/rehydration approach is further extended to (2,2'-bpy)CrF3·2H2O with S = 3/2 1D chains, thus opening the possibility of obtaining other low-dimensional spin lattices.

Direct C-C Double Bond Cleavage of Alkenes Enabled by Highly Dispersed Cobalt Catalyst and Hydroxylamine.

The utilization of a single-atom catalyst to break C-C bonds merges the merits of homogeneous and heterogeneous catalysis and presents an intriguing pathway for obtaining high-value-added products. Herein, a mild, selective, and sustainable oxidative cleavage of alkene to form oxime ether or nitrile was achieved by using atomically dispersed cobalt catalyst and hydroxylamine. Diversified substrate patterns, including symmetrical and unsymmetrical alkenes, di- and tri-substituted alkenes, and late-stage functionalization of complex alkenes were demonstrated. The reaction was successfully scaled up and demonstrated good performance in recycling experiments. The hot filtration test, catalyst poisoning and radical scavenger experiment, time kinetics, and studies on the reaction intermediate collectively pointed to a radical mechanism with cobalt/acid/O2 promoted C-C bond cleavage as the key step.

SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53.

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.

KMB4O6F3 (M = Co, Fe): two-dimensional magnetic fluorooxoborates with triangular lattices directed by triangular BO3 units.

Frustrated magnetic systems are of great interest owing to their spin liquid state for application in quantum computing. However, experimentally, spin liquid has not been realized. Thus, experimental explorations of frustrated magnetic systems including triangular lattices are still urgent, particularly for directed synthesis compared to random exploration. Herein, for the first time, directed by the use of a triangular unit of the BO3 anion group, two novel layered magnetic fluorooxoborates KMB4O6F3 (M = Co 1, Fe 2) with triangular lattices have been hydrothermally synthesized and characterized. Compounds 1 and 2 are isostructural and crystallize in the P21/c space group with layered magnetic triangular lattices, which are further separated by K+ ions. Magnetic susceptibility curves of both 1 and 2 show no λ-anomaly peak down to a low temperature of 2 K in the absence of a magnetic long-range ordering transition, which are further confirmed by the heat capacity results. The magnetic-field dependence of magnetization at 2 K shows saturation of 2.20µB for 1 and 4.24µB for 2, respectively, at 7 T, after roughly subtracting the Van Vleck paramagnetic contribution. Further in-depth investigation of the underlying physics at a lower temperature below 2 K would be subsequently performed. Moreover, thermal stability and FT-IR and UV-vis-NIR spectroscopy with optical bandgap properties are also reported. Most importantly, our work provides a promising method to experimentally realize specific magnetic lattices (e.g. triangular lattices) directed by the use of triangular groups (e.g. BO3) as the functional unit.

Identification of M2-like macrophage-related signature for predicting the prognosis, ecosystem and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is one of the most common malignancies worldwide, representing a big health-care challenge globally. M2-like macrophages are significantly correlated with tumor progression, metastasis and treatment resistance. METHODS: Integrative 10 machine learning algorithms were performed to developed a M2-like macrophage related prognostic signature (MRPS). Single-cell RNA-sequencing analysis was performed to dissect the ecosystem of HCC. Several approaches, including TIDE score, immunophenoscore, TMB score and tumor escape score were used to evaluate the predictive role of MRPS in immunology response. RESULTS: The optimal MRPS constructed by the combination of stepCox + superPC algorithm served as an independent risk factor and showed stable and powerful performances in predicting the overall survival rate of HCC patients with 2-, 3-, and 4-year AUCs of 0. 763, 0.751, and 0.699 in TCGA cohort. HCC patients with low risk score possessed a more interaction of immunoactivated cells, including NK, CD8+ cytotoxic T, and activated B, and a less interaction of immunosuppressive cells, including Treg, CD4+ exhauster T, and M2-like macrophage. Low risk score indicated a higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score and lower tumor escape score in HCC, suggesting a better immunotherapy response. The IC50 value of docetaxel, gemcitabine, crizotinib and Osimertinib in HCC with high risk score were lower versus that with low risk score. HCC patients with high risk score had a higher score of cancer-related hallmarks, including angiogenesis, DNA repair, EMT, glycolysis, and NOTCH signaling. CONCLUSION: Our study proposed a novel MRPS for predicting the prognosis, ecosystem and immunotherapy response in HCC.

Clinical Efficacy Evaluation of Ultrasound-Guided C2 Dorsal Root Nerve Pulsed Radiofrequency Combined with Stellate Ganglion Block in the Treatment of Cervicogenic Headache: A Retrospective Cohort Study.

Purpose: To explore the therapeutic effect of C2 dorsal root ganglion pulsed radiofrequency (PRF) combined with stellate ganglion block (SGB) in patients with cervicogenic headache (CEH). Patients and Methods: We retrospectively reviewed 90 patients diagnosed with CEH who were admitted to our hospital between May 2019 and May 2022. All patients were divided into three groups (n = 30 each) according to the actual treatment method used: ultrasound-guided SGB, ultrasound-guided C2 dorsal root ganglion PRF treatment, and ultrasound-guided C2 dorsal root ganglion PRF combined with SGB treatment. Patients' pain intensity, sleep, and mood changes were assessed by statistically analyzing their pain visual analog scale (VAS), Pittsburgh Sleep Quality Inventory (PSQI), and short-form McGill Pain Questionnaire affective item scores before and after treatment. Results: The post-treatment VAS, PSQI, and McGill scores were significantly decreased in all patients (P < 0.05), and all three scores in ultrasound-guided C2 dorsal root ganglion PRF combined with SGB were lower than those in ultrasound-guided SGB alone and ultrasound-guided C2 dorsal root ganglion PRF alone (P < 0.05). Conclusion: The use of ultrasound-guided C2 dorsal root ganglion PRF combined with SGB in patients with CHE is effective in alleviating pain and improving sleep, and deserves to be replicated in the clinic.

Combining bulk and single-cell RNA-sequencing data to develop an NK cell-related prognostic signature for hepatocellular carcinoma based on an integrated machine learning framework.

BACKGROUND: The application of molecular targeting therapy and immunotherapy has notably prolonged the survival of patients with hepatocellular carcinoma (HCC). However, multidrug resistance and high molecular heterogeneity of HCC still prevent the further improvement of clinical benefits. Dysfunction of tumor-infiltrating natural killer (NK) cells was strongly related to HCC progression and survival benefits of HCC patients. Hence, an NK cell-related prognostic signature was built up to predict HCC patients' prognosis and immunotherapeutic response. METHODS: NK cell markers were selected from scRNA-Seq data obtained from GSE162616 data set. A consensus machine learning framework including a total of 77 algorithms was developed to establish the gene signature in TCGA-LIHC data set, GSE14520 data set, GSE76427 data set and ICGC-LIRI-JP data set. Moreover, the predictive efficacy on ICI response was externally validated by GSE91061 data set and PRJEB23709 data set. RESULTS: With the highest C-index among 77 algorithms, a 11-gene signature was established by the combination of LASSO and CoxBoost algorithm, which classified patients into high- and low-risk group. The prognostic signature displayed a good predictive performance for overall survival rate, moderate to high predictive accuracy and was an independent risk factor for HCC patients' prognosis in TCGA, GEO and ICGC cohorts. Compared with high-risk group, low-risk patients showed higher IPS-PD1 blocker, IPS-CTLA4 blocker, common immune checkpoints expression but lower TIDE score, which indicated low-risk patients might be prone to benefiting from ICI treatment. Moreover, a real-world cohort, PRJEB23709, also revealed better immunotherapeutic response in low-risk group. CONCLUSIONS: Overall, the present study developed a gene signature based on NK cell-related genes, which offered a novel platform for prognosis and immunotherapeutic response evaluation of HCC patients.

Minimally invasive enucleation versus open enucleation for benign or low-grade malignant pancreatic neoplasms: Effects on clinical outcomes and quality of life.

Introduction: The efficacy and safety of minimally invasive pancreatic enucleation (PE) have rarely been investigated. This study aimed to compare the perioperative and long-term outcomes of minimally invasive enucleation (MIEn) with those of open enucleation (OEn) for benign/low-grade malignant pancreatic neoplasms. Patients and Methods: Data collected from patients who underwent PE between January 2011 and June 2020 at our centre were analysed. Results: Forty-two patients who underwent MIEn (10 - robot-assisted and 32 - laparoscopic) and 47 who underwent OEn were included in this study. Compared with the OEn group, the MIEn group showed shorter operation time (147.6 ± 71.3 min vs. 183.1 ± 64.3 min), shorter post-operative hospital stay (11.5 ± 3.9 days vs. 13.4 ± 4.2 days), shorter off-bed activity time (2.9 ± 0.9 days vs. 3.7 ± 1.0 days) and lower estimated blood loss (EBL) (118.5 ± 59.2 mL vs. 153.1 ± 85.0 mL). Overall complication rate (47.6% vs. 55.3%), overall post-operative pancreatic fistula (POPF) rate (40.5% vs. 44.7%) and Grade B + C POPF rate (11.9% vs. 19.1%) were similar in both the groups. For neoplasms located in the proximal pancreas, MIEn showed more favourable perioperative outcomes than OEn. Unlike MIEn for superficial neoplasms, MIEn for neoplasms deeply embedded in the pancreas resulted in a longer operative time and tended to increase EBL and the incidence of complications and POPF. During the follow-up period, no significant differences were observed between these two groups in terms of pancreatic function or quality of life. Conclusions: Compared to OEn, MIEn is effective and safe for patients with benign or low-grade malignant pancreatic neoplasms. However, MIEn for embedded pancreatic neoplasms is recommended only in experienced centres because of the high rates of complications and POPF.

RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identifying factors and mechanisms that control PKM alternative splicing is significant for overcoming the current challenges in ATC treatment. RESULTS: In this study, the expression of RBX1 was largely enhanced in the ATC tissues. Our clinical tests suggested that high RBX1 expression was significantly related to poor survival. The functional analysis indicated that RBX1 facilitated the metastasis of ATC cells by enhancing the Warburg effect, and PKM2 played a key role in RBX1-mediated aerobic glycolysis. Furthermore, we confirmed that RBX1 regulates PKM alternative splicing and promotes the PKM2-mediated Warburg effect in ATC cells. Moreover, ATC cell migration and aerobic glycolysis induced by RBX1-mediated PKM alternative splicing are dependent on the destruction of the SMAR1/HDAC6 complex. RBX1, as an E3 ubiquitin ligase, degrades SMAR1 in ATC through the ubiquitin-proteasome pathway. CONCLUSION: Overall, our study identified the mechanism underlying the regulation of PKM alternative splicing in ATC cells for the first time and provides evidence about the effect of RBX1 on cellular adaptation to metabolic stress.

MIO3F (M = Co and Ni): Magnetic Iodate Fluorides with Zigzag Chains.

The iodate anion group has been widely used for design and synthesis of functional materials including nonlinear optical materials but rarely for magnetic materials. Particularly, none of magnetic iodate fluorides has been reported yet. In this work, first, two novel magnetic iodate fluorides MIO3F (M = Co 1 and Ni 2) have been synthesized by a hydrothermal method and characterized by magnetic susceptibility, magnetization, and heat capacity measurements as well as thermogravimetry, Fourier transform infrared spectroscopy (FT-IR), and ultraviolet-visible-near-infrared (UV-vis-NIR) spectroscopy. Compounds 1 and 2 are isostructural and crystallize in the monoclinic space group P21/n with alternating M2+-F2-M2+-O2-M2+ zigzag spin chains along the b axis, which are further separated by triangular IO3 groups in the ab plane. Magnetic susceptibilities suggest that 1 exhibits an antiferromagnetic long-range order (LRO) at 16.5 K, confirmed by heat capacity results with released entropy consistent with the theoretical value for a pseudo-spin of 1/2 for Co2+ at low temperatures. Meanwhile, 2 displays a broad maximum around 10.5 K for low dimensional magnetism followed by a sharp peak at 5.7 K indicating the occurrence of an LRO transition, in good agreement with the heat capacity measurement. Field-dependent magnetizations show an obvious spin-flop transition around 4.5 T and a magnetic hysteresis loop between 4.5 and 7 T for 1, but only a slight slope change could be observed around 2.3 T for 2. Thermal stability, FT-IR, and UV-vis-NIR spectroscopy of 1 and 2 are also reported.

LncRNA SNHG1 Facilitates Tumor Proliferation and Represses Apoptosis by Regulating PPARγ Ubiquitination in Bladder Cancer.

BACKGROUND: Long noncoding RNAs regulate various biological effects in the progression of cancers. We found that the expression of SNHG1 was significantly up-regulated in bladder cancer after analyzing data obtained from TCGA and GEO. However, the potential role of SNHG1 remains to be investigated in bladder cancer. It was validated that SNHG1 was overexpressed in bladder cancer tissues detected by qRT-PCR and FISH, which was also associated with poor clinical outcome. Additionally, SNHG1 was verified to facilitate tumor proliferation and repress apoptosis in vitro and in vivo. RESULTS: SNHG1 could act as a competitive endogenous RNA and decrease the expression of murine double minute 2 (MDM2) by sponging microRNA-9-3p. Furthermore, MDM2 induced ubiquitination and degradation of PPARγ that contributed to the development of bladder cancer. CONCLUSIONS: the study elucidated that SNHG1 played an important role in bladder cancer and provided a potential therapeutic target for bladder cancer.

Simple cholecystectomy is an adequate treatment for grade I T1bN0M0 gallbladder carcinoma: Evidence from 528 patients.

BACKGROUND: T1b gallbladder carcinoma (GBC) is defined as a tumor that invades the perimuscular connective tissue without extension beyond the serosa or into the liver. However, controversy still exists over whether patients with T1b GBC should undergo cholecystectomy alone or radical GBC resection. AIM: To explore the optimal surgical approach in patients with T1b gallbladder cancer of different pathological grades. METHODS: Patients with T1bN0M0 GBC who underwent surgical treatment between 2000 and 2017 were included in the Surveillance, Epidemiology, and End Results database. The Kaplan-Meier method and log-rank test were used to analyze the overall survival (OS) and disease-specific survival (DSS) of patients with T1b GBC of different pathological grades. Cox regression analysis was used to identify independent predictors of mortality and explore the selection of surgical methods in patients with T1b GBC of different pathological grades and their relationship with prognosis. RESULTS: Of the 528 patients diagnosed with T1bN0M0 GBC, 346 underwent simple cholecystectomy (SC) (65.5%), 131 underwent SC with lymph node resection (SC + LN) (24.8%), and 51 underwent radical cholecystectomy (RC) (9.7%). Without considering the pathological grade, both the OS (P < 0.001) and DSS (P = 0.003) of T1b GBC patients who underwent SC (10-year OS: 27.8%, 10-year DSS: 55.1%) alone were significantly lower than those of patients who underwent SC + LN (10-year OS: 35.5%, 10-year DSS: 66.3%) or RC (10-year OS: 50.3%, 10-year DSS: 75.9%). Analysis of T1b GBC according to pathological classification revealed no significant difference in OS and DSS between different types of procedures in patients with grade I T1b GBC. In patients with grade II T1b GBC, obvious survival improvement was observed in the OS (P = 0.002) and DSS (P = 0.039) of those who underwent SC + LN (10-year OS: 34.6%, 10-year DSS: 61.3%) or RC (10-year OS: 50.5%, 10-year DSS: 78.8%) compared with those who received SC (10-year OS: 28.1%, 10-year DSS: 58.3%). Among patients with grade III or IV T1b GBC, SC + LN (10-year OS: 48.5%, 10-year DSS: 72.2%), and RC (10-year OS: 80%, 10-year DSS: 80%) benefited OS (P = 0.005) and DSS (P = 0.009) far more than SC (10-year OS: 20.1%, 10-year DSS: 38.1%) alone. CONCLUSION: Simple cholecystectomy may be an adequate treatment for grade I T1b GBC, whereas more extensive surgery is optimal for grades II-IV T1b GBC.

Identification of a Necroptosis-Related Prognostic Signature and Associated Regulatory Axis in Liver Hepatocellular Carcinoma.

Background: Liver hepatocellular carcinoma (LIHC) ranks the sixth in global cancer incidence with poor prognosis. Necroptosis is a kind of regulated cell death and has been proved to be of significance in cancer occurrence and progression. However, few studies comprehensively discuss the potential applications of necroptosis-related genes (NRGs) in the prognostic evaluation and immunotherapy of LIHC. Methods: The prognostic signature in the present study was built up using LASSO Cox regression analysis. Integrated bioinformatics tools were utilized to explore the potential mRNA-miRNA-lncRNA regulatory axis in LIHC. Furthermore, qRT-PCR method was used to verify the EZH2 expression in LIHC tissues. Furthermore, prognostic performance of EZH2 in LIHC was assessed by Kaplan-Meier method. Results: A total of 14 NRGs were differentially expressed in LIHC tissues. The overall genetic mutation status of these NRGs in LIHC was also shown. NRGs were significantly correlated with programmed necrotic cell death, as well as Toll-like receptor signaling pathway in GO and KEGG pathway analysis. Kaplan-Meier analysis revealed that ALDH2, EZH2, NDRG2, PGAM5, RIPK1, and TRAF2 were related to the prognosis. A prognostic signature was constructed by these six genes and showed medium to high accuracy in the prediction of LIHC patients' prognosis. Further analysis revealed that NRGs were correlated with pathological stage, immune infiltration, and drug resistance in LIHC. Moreover, we identified a potential lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis in LIHC, which might affect the progression of LIHC. qRT-PCR suggested a higher mRNA level of EZH2 in LIHC tissues. And a poor overall survival rate was detected in LIHC patients with high EZH2 expression. Moreover, EZH2 expression and cancer stage were identified as the independent risk factors affecting LIHC patients' prognosis. Conclusion: In the present study, we conducted comprehensive bioinformatic analyses and built up a necroptosis-related prognostic signature containing four genes (ALDH2, EZH2, NDRG2, and PGAM5) for patients with LIHC, and this prognostic signature showed a medium to high predictive accuracy. And our study also identified a lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis, which might be of great significance in LIHC progression. In addition, based on the data from our center, the result of qRT-PCR and survival analysis showed a higher mRNA level of EZH2 in LIHC tissues and an unfavorable prognosis in high EZH2 expression group, respectively.

NCAPG promotes the proliferation of hepatocellular carcinoma through the CKII-dependent regulation of PTEN.

BACKGROUND: NCAPG, non-SMC subunit in the concentrate I complex, might promote the proliferation of hepatocellular carcinoma (HCC), but the mechanism is unclear. The aim of this study was to explore how NCAPG affects PTEN to influence the proliferation of HCC. METHODS: Western blotting, qRT-PCR and immunohistochemistry were used to detect NCAPG expression in HCC tissues. The effect of NCAPG on the proliferation of HCC cell lines was evaluated using an EdU incorporation assay, a Cell Counting Kit-8 assay and Fluorescence in situ hybridization (FISH). BALB/c-nu/nu mice were used for the in vivo proliferation experiment. Transcriptome sequencing was used to determine the relationship between NCAPG and PTEN. Immunocoprecipitation-mass spectrometry (IP-MS), proteomic sequencing and Co-immunoprecipitation (CO-IP) were used to identify and examine the interaction between the NCAPG and CKII proteins. RESULTS: We confirmed that NCAPG was abnormally overexpressed in HCC and promoted the proliferation of HCC cells. Transcriptome sequencing revealed that NCAPG inhibited the transcription of PTEN and promoted the activation of the PI3K-AKT pathway. We found a close association between NCAPG and CKII through proteomic sequencing; their interaction was confirmed by Co-IP. There was a positive correlation between NCAPG and CKII that promoted the phosphorylation of PTEN and thus inhibited its transcription and functions. We also proved that CKII was the key factor in the induction of proliferation by NCAPG. CONCLUSION: We revealed the mechanism by which NCAPG regulates the proliferation of HCC: NCAPG inhibits PTEN through its interaction with CKII, and then activates the PI3K-AKT pathway to promote the proliferation of HCC.

Succinylation Inhibits the Enzymatic Hydrolysis of the Extracellular Matrix Protein Fibrillin 1 and Promotes Gastric Cancer Progression.

Extracellular matrix (ECM) remodeling is crucial in the regulation of gastric cancer (GC) progression. This work aims to reveal novel posttranslational modifications and their relevant mechanisms in GC. In 3D matrix culture and animal models, it is found that fibrillin 1 (FBN1) expression is increased in advanced GC and has succinylation modification. The succinylation modification of FBN1 blocks its degradation by matrix metalloproteinases (MMPs). The long-term accumulation and deposition of FBN1 enhance tumor progression by activating TGF-ß1 and intracellular PI3K/Akt pathway. The FBN1 succinylation site monoclonal antibody can effectively intervene the effect of succinylation modification and inhibit GC progression. FBN1 is specifically upregulated in the progression of GC compared with other tumors. In conclusion, FBN1 is widely present in the form of K672-succinylated modifications in GC. Besides, the succinyl group of FBN1 blocks its binding to MMP2, inhibits its degradation by MMP2, and leads to the accumulation of FBN1, which poses a long-term risk to the poor prognosis of GC.

A Pyroptosis-Related Gene Signature to Predict Patients' Prognosis and Immune Landscape in Liver Hepatocellular Carcinoma.

BACKGROUND: Liver hepatocellular carcinoma (LIHC) is a malignance with high incidence and recurrence. Pyroptosis is a programed cell death pattern which both activates the effective immune response and causes cell damage. However, their potential applications of pyroptosis-related genes (PRGs) in the prognostic evaluation and immunotherapy of LIHC are still rarely discussed. METHODS: Comprehensive bioinformatics analyses based on TCGA-LIHC dataset were performed in the current study. RESULTS: A total of 33 PRGs were selected to perform the current study. Of these 33 PRGs, 26 PRGs with upregulation or downregulation in LIHC tissues were identified. We also summarized the related genetic mutation variation landscape. GO and KEGG pathway analysis demonstrated that these 26 PRGs were primarily associated with pyroptosis, positive regulation of interleukin-1 beta production, and NOD-like receptor signaling pathway. An unfavorable OS appeared in LIHC patients with high CASP3, CASP4, CASP6, CASP8, GPX4, GSDMA, GSDME, NLRP3, NLRP7, NOD1, NOD2, PLCG1, and SCAF11 expression and low NLRP6 expression. A prognostic signature constructed by the above 14 prognostic PRGs had moderate to high accuracy to predict LIHC patients' prognosis. And risk score was correlated with the expression of CASP6, CASP8, GPX4, GSDMA, GSDME, NLRP6, and NOD2. Of these 7 genes, CASP8 was identified as the core gene in PPI network. Moreover, lncRNA MIR17HG/hsa-miRNA-130b-3p/CASP8 regulatory axis in LIHC was also detected. CONCLUSIONS: The current study indicated the crucial role of PRGs in the prognostic evaluation of LIHC patients and their correlations with tumor microenvironment in LIHC.

Identifying a Novel Defined Pyroptosis-Associated Long Noncoding RNA Signature Contributes to Predicting Prognosis and Tumor Microenvironment of Bladder Cancer.

Background: Bladder cancer (BLCA) is a common malignant tumor of the urinary tract, which is the sixth most common cancer among men. Numerous studies suggested that pyroptosis and long noncoding RNAs (lncRNAs) played an essential role in the development of cancers. However, the role of pyroptosis-related lncRNAs in BLCA and their prognostic value are still unclear. Methods: In this study, we constructed a signature model through least absolute shrinkage and selection operator (LASSO) Cox regression analysis and Cox univariate analysis based on The Cancer Genome Atlas (TCGA) database. The expression of 12 pyroptosis-related lncRNAs was also confirmed by qRT-PCR in BLCA cell lines. TIMER, XCELL, QUANTISEQ, MCPCOUNTER, EPIC, and CIBERSORT R script were applied to quantify the relative proportions of infiltrating immune cells. Correlation coefficients were computed by Spearman analyses. The Kaplan-Meier method, Cox regression model, and log-rank tests were used to evaluate the prognostic value. The R package of pRRophetic was used to predict IC50 of common chemotherapeutic agents. Results: A total of 12 pyroptosis-related lncRNAs with great prognosis value were identified. The expression was investigated by qRT-PCR in four BLCA cell lines. Then, 126 cases were identified as high-risk group, and 277 cases were identified as low-risk group based on the cutoff point. Patients in the low-risk group showed a significant survival advantage. Furthermore, we found that clinical features were significantly related to the risk score. As well, based on the C-index values, a nomogram was constructed. The gene set enrichment analysis (GSEA) results showed that mitogen-activated protein kinase (MAPK) signaling, transforming growth factor (TGF)-ß signaling, and WNT signaling were with important significance in the high-risk group. Moreover, we found that riskscore was positively correlated with M0 macrophages and M2 macrophages. Conclusions: In conclusion, our study indicated that pyroptosis is closely connected to BLCA. The riskscore generated from the expression of 12 pyroptosis-related lncRNAs was evaluated by various clinical features including survival status, tumor microenvironment, clinicopathological characteristic, and chemotherapy. It may offer a significant basis for future studies.

Circadian Clock Genes Are Correlated with Prognosis and Immune Cell Infiltration in Colon Adenocarcinoma.

BACKGROUND: Colon adenocarcinoma (COAD) is a malignancy with a high incidence and is associated with poor quality of life. Dysfunction of circadian clock genes and disruption of normal rhythms are associated with the occurrence and progression of many cancer types. However, studies that systematically describe the prognostic value and immune-related functions of circadian clock genes in COAD are lacking. METHODS: Genomic data obtained from The Cancer Genome Atlas (TCGA) database was analyzed for expression level, mutation status, potential biological functions, and prognostic performance of core circadian clock genes in COAD. Their correlations with immune infiltration and TMB/MSI score were analyzed by Spearman's correlation analysis. Pearson's correlation analysis was performed to analyze their associations with drug sensitivity. Lasso Cox regression analysis was performed to construct a prognosis signature. Moreover, an mRNA-miRNA-lncRNA regulatory axis was also detected by ceRNA network. RESULTS: In COAD tissues, the mRNA levels of CLOCK, CRY1, and NR1D1 were increased, while the mRNA levels of ARNTL, CRY2, PER1, PER3, and RORA were decreased. We also summarized the relative genetic mutation variation landscape. GO and KEGG pathway analyses demonstrated that these circadian clock genes were primarily correlated with the regulation of circadian rhythms and glucocorticoid receptor signaling pathways. COAD patients with high CRY2, NR1D1, and PER2 expression had worse prognosis. A prognostic model constructed based on the 9 core circadian clock genes predicted the COAD patients' overall survival with medium to high accuracy. A significant association between prognostic circadian clock genes and immune cell infiltration was found. Moreover, the lncRNA KCNQ1OT1/hsa-miRNA-32-5p/PER2/CRY2 regulatory axis in COAD was also detected through a mRNA-miRNA-lncRNA network. CONCLUSION: Our results identified CRY2, NR1D1, and PER2 as potential prognostic biomarkers for COAD patients and correlated their expression with immune cell infiltration. The lncRNA KCNQ1OT1/hsa-miRNA-32-5p/PER2/CRY2 regulatory axis was detected in COAD and might play a vital role in the occurrence and progression of COAD.