Energy stress-induced circDDX21 promotes glycolysis and facilitates hepatocellular carcinogenesis.

Cancer cells undergo metabolic reprogramming in response to hostile microenvironments, such as energy stress; however, the underlying mechanisms remain largely unclear. It is also unknown whether energy stress-responsive circular RNA (circRNA) is involved in the regulation of glucose metabolism. Here we report that circDDX21 is upregulated in response to glucose deprivation by the transcription factor c-Myc. Functionally, circDDX21 is shown to promote glycolysis by increasing PGAM1 expression. Mechanistically, circDDX21 interacts with the RNA binding protein PABPC1, disrupting its association with the ubiquitin E3 ligase MKRN3. This disassociation attenuates MKRN3-mediated PABPC1 ubiquitination and enhances the binding of PABPC1 to PGAM1 mRNA, thereby leading to PGAM1 mRNA stabilization. The ability of the circDDX21-PGAM1 axis to promote hepatocellular carcinogenesis is validated in a xenograft mouse model. Additionally, in clinical hepatocellular carcinoma tissues, there is a positive correlation between circDDX21 and PGAM1 expression. These findings establish circDDX21 as an important regulator of glycolysis and suggest circDDX21 as a potential therapeutic target for hepatocellular carcinoma.

Global rigorous coupled wave analysis for design of multilayer metasurface absorbers.

In this work, a novel Global NV-ETM RCWA method is proposed to accelerate the optimization of the periodic stepped radar absorbing structure. This method is based on the rigorous coupled-wave analysis (RCWA) utilizing the normal vector field (NV) and enhanced transmittance matrix (ETM) approach. The NV field dramatically improves the convergence rate for both dielectric and magnetic metasurfaces. The Global NV-ETM RCWA algorithm is developed to further accelerate the complete search calculations. Using the proposed method, the periodic stepped radar absorbing structures are efficiently optimized to realize the entire band absorption in 2-18 GHz. The optimization results demonstrate the Global NV-ETM RCWA method significantly increase the computational efficiency, with a 38-fold improvement over direct NV-ETM RCWA calculations when the truncation order N=3. This method provides a powerful tool for designing metasurface absorbers with various desired functionalities.

MLF2 Negatively Regulates P53 and Promotes Colorectal Carcinogenesis.

Inactivation of the p53 pathway is linked to a variety of human cancers. As a critical component of the p53 pathway, ubiquitin-specific protease 7 (USP7) acts as a deubiquitinase for both p53 and its ubiquitin E3 ligase mouse double minute 2 homolog. Here, myeloid leukemia factor 2 (MLF2) is reported as a new negative regulator of p53. MLF2 interacts with both p53 and USP7. Via these interactions, MLF2 inhibits the binding of USP7 to p53 and antagonizes USP7-mediated deubiquitination of p53, thereby leading to p53 destabilization. Functionally, MLF2 plays an oncogenic role in colorectal cancer, at least partially, via the negative regulation of p53. Clinically, MLF2 is elevated in colorectal cancer and its high expression is associated with poor prognosis in patients with colorectal cancer. In wild-type-p53-containing colorectal cancer, MLF2 and p53 expressions are inversely correlated. These findings establish MLF2 as an important suppressor of p53 function. The study also reveals a critical role for the MLF2-p53 axis in promoting colorectal carcinogenesis.

Online calculators for predicting the risk of anastomotic stricture after hepaticojejunostomy for bile duct injury after cholecystectomy: a multicenter retrospective study.

BACKGROUND: Anastomotic stricture is a common underlying cause of long-term morbidity after hepaticojejunostomy (HJ) for bile duct injury (BDI) following cholecystectomy. However, there are no methods for predicting stricture risk. This study was aimed at establishing two online calculators for predicting anastomotic stricture occurrence (ASO) and stricture-free survival (SFS) in this patient population. METHODS: The clinicopathological characteristics and follow-up information of patients who underwent HJ for BDI after cholecystectomy from a multi-institutional database were reviewed. Univariate and multivariate analyses of the risk factors of ASO and SFS were performed in the training cohort. Two nomogram-based online calculators were developed and validated by internal bootstrapping resamples ( n =1000) and an external cohort. RESULTS: Among 220 screened patients, 41 (18.64%) experienced anastomotic strictures after a median follow-up of 110.7 months. Using multivariate analysis, four variables, including previous repair, sepsis, HJ phase, and bile duct fistula, were identified as independent risk factors associated with both ASO and SFS. Two nomogram models and their corresponding online calculators were subsequently developed. In the training cohort, the novel calculators achieved concordance indices ( C -indices) of 0.841 and 0.763 in predicting ASO and SFS, respectively, much higher than those of the above variables. The predictive accuracy of the resulting models was also good in the internal ( C -indices: 0.867 and 0.821) and external ( C -indices: 0.852 and 0.823) validation cohorts. CONCLUSIONS: The two easy-to-use online calculators demonstrated optimal predictive performance for identifying patients at high risk for ASO and with dismal SFS. The estimation of individual risks will help guide decision-making and long-term personalized surveillance.

The RNA binding protein RALY suppresses p53 activity and promotes lung tumorigenesis.

The tumor suppressor p53 plays a pivotal role in tumor prevention. The activity of p53 is mainly restrained by the ubiquitin E3 ligase Mdm2. However, it is not well understood how the Mdm2-p53 pathway is intricately regulated. Here we report that the RNA binding protein RALY functions as an oncogenic factor in lung cancer. RALY simultaneously binds to Mdm2 and the deubiquitinating enzyme USP7. Via these interactions, RALY not only stabilizes Mdm2 by stimulating the deubiquitinating activity of USP7 toward Mdm2 but also increases the trans-E3 ligase activity of Mdm2 toward p53. Consequently, RALY enhances Mdm2-mediated ubiquitination and degradation of p53. Functionally, RALY promotes lung tumorigenesis, at least partially, via negative regulation of p53. These findings suggest that RALY destabilizes p53 by modulating the function of Mdm2 at multiple levels. Our study also indicates a critical role for RALY in promoting lung tumorigenesis via p53 inhibition.

Characterization of SHCBP1 to prognosis and immunological landscape in pan-cancer: novel insights to biomarker and therapeutic targets.

BACKGROUND: Previous studies have revealed the significant roles of SHC SH2 domain-binding protein 1 (SHCBP1) in occurrence and progression of cancers, but there is no pan-cancer analysis of SHCBP1. METHODS: In this study, we explored the potential carcinogenic role of SHCBP1 across 33 tumors from the TCGA and GTEx databases. We investigated SHCBP1 expression, prognosis, genetic alterations, tumor mutational burden (TMB) score, microsatellite instability (MSI) and tumor microenvironment from TIMER2, GEPIA2, UALCAN and cBioPortal databases. Moreover, the cellular functions and potential mechanisms were evaluated by GO and KEGG analysis. Besides, the mRNA expression of SHCBP1 was examined using qRT-PCR assay in gastrointestinal cancers. RESULTS: SHCBP1 was significantly upregulated in various cancers, and apparent relationship existed between SHCBP1 and survival prognosis in patients. The TMB, MSI, and tumor microenvironment analysis indicated that SHCBP1 was closely related to immune checkpoints, immune targets, as well as CD4+ naive T cell, CD8+ T cell, and neutrophil. Moreover, the cellular functions of SHCBP1 were mainly in regulating cell cycle motor protein activity. In addition, we validated that SHCBP1 mRNA expression was over-expressed in gastrointestinal cancers. CONCLUSIONS: This study was the first to systematically determine the prognostic value of SHCBP1, providing a forward-looking perspective on immunotherapy and cellular processes in pan-cancer.

Machine Learning for Predicting Distant Metastasis of Medullary Thyroid Carcinoma Using the SEER Database.

Objectives: We aimed to establish an effective machine learning (ML) model for predicting the risk of distant metastasis (DM) in medullary thyroid carcinoma (MTC). Methods: Demographic data of MTC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database of the National Institutes of Health between 2004 and 2015 to develop six ML algorithm models. Models were evaluated based on accuracy, precision, recall rate, F1-score, and area under the receiver operating characteristic curve (AUC). The association between clinicopathological characteristics and target variables was interpreted. Analyses were performed using traditional logistic regression (LR). Results: In total, 2049 patients were included and 138 developed DM. Multivariable LR showed that age, sex, tumor size, extrathyroidal extension, and lymph node metastasis were predictive features for DM in MTC. Among the six ML models, the random forest (RF) had the best predictability in assessing the risk of DM in MTC, with an accuracy, precision, recall rate, F1-score, and AUC higher than those of the traditional binary LR model. Conclusion: RF was superior to traditional LR in predicting the risk of DM in MTC and can provide a valuable reference for clinicians in decision-making.

2D rigorous coupled wave analysis with adaptive spatial resolution for a multilayer periodic structure.

We utilize the 2D modal solution of rigorous coupled wave analysis with adaptive spatial resolution to enhance the reliability of standard RCWA for multilayer gratings with metal-dielectric structures. The conversion relation in modal solutions between the Cartesian system and the transformed system is for the first time established. Based on the proposed conversion relation, the modal solution of the metal-dielectric structure obtained in the transformed system can match the boundary conditions with modal solutions of other different grating layers in the Cartesian system. Numerical results show that even for metal patches in microwave band, the above method can still achieve good convergence and is perfectly suitable for multi-layer structure calculation.

Rigorous coupled wave analysis upgraded with combined boundary conditions method for 2D metamaterials in microwave.

We combine rigorous coupled wave analysis (RCWA) and combined boundary conditions method (CBCM) to analyze optical properties of two-dimensional periodic metamaterial grating with arbitrary shapes in microwave domain, and the adaptive spatial resolution (ASR) function is introduced to increase convergence especially for the crossed metamaterial gratings. The numerical results show that RCWA with CBCM can get the correct convergence result and distinguish the contribution of the grating lobes to the total transmission and reflection. The ASR technique improves dramatically the convergence speed of crossed grating. This method provides a more effective computational tool for the design of metamaterial grating in microwave domain.

NCAPG facilitates colorectal cancer cell proliferation, migration, invasion and epithelial-mesenchymal transition by activating the Wnt/ß-catenin signaling pathway.

BACKGROUND: The condensation complex gene non-SMC condensin I complex subunit G(NCAPG), a cell cycle-associated condensin, is over-expressed in various cancers. However, its biological function in colorectal cancer (CRC) has yet to be deciphered. In this study, we investigated the role of NCAPG in CRC progression. METHODS: Tissues and cells were used to measure NCAPG expression levels and their association with clinicopathological characteristics. NCAPG silencing and overexpression in CRC cells were used to measure its effect on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) progression. In addition, mRNA, and protein expression levels of key EMT biomarkers were measured. The underlying mechanism of NCAPG modulating CRC progression was further explored using western blotting, co-immunoprecipitation (CO-IP), and immunofluorescence (IF) assays. RESULTS: NCAPG was over-expressed in CRC tissues and cell lines. High expression levels were associated with differentiation levels, lymph metastasis, and vascular invasion in patients. NCAPG silencing suppressed, while NCAPG overexpression promoted the proliferative, migration, and invasive capacity of HCT116 and SW480 cells. Mechanistically, we discovered that NCAPG participated in regulating the EMT process and the Wnt/ß-catenin signaling pathway to facilitate CRC invasion and metastasis. Additional experiments demonstrated that NCAPG activated the Wnt/ß-catenin signaling pathway by binding to ß-catenin in CRC cells. CONCLUSION: NCAPG acts as an oncogene involved in the development and progression of CRC by binding to ß-catenin to activate the Wnt/ß-catenin signaling pathway.

Reciprocal modulation of long noncoding RNA EMS and p53 regulates tumorigenesis.

p53 plays a central role in tumor suppression. Emerging evidence suggests long noncoding RNA (lncRNA) as an important class of regulatory molecules that control the p53 signaling. Here, we report that the oncogenic lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and p53 mutually repress each other's expression. EMS is negatively regulated by p53. As a direct transcriptional repression target of p53, EMS is surprisingly shown to inhibit p53 expression. EMS associates with cytoplasmic polyadenylation element-binding protein 2 (CPEB2) and thus, disrupts the CPEB2-p53 mRNA interaction. This disassociation attenuates CPEB2-mediated p53 mRNA polyadenylation and suppresses p53 translation. Functionally, EMS is able to exert its oncogenic activities, at least partially, via the CPEB2-p53 axis. Together, these findings reveal a double-negative feedback loop between p53 and EMS, through which p53 is finely controlled. Our study also demonstrates a critical role for EMS in promoting tumorigenesis via the negative regulation of p53.

c-Myc-activated USP2-AS1 suppresses senescence and promotes tumor progression via stabilization of E2F1 mRNA.

The c-Myc oncoprotein plays a prominent role in cancer initiation, progression, and maintenance. Long noncoding RNAs (lncRNAs) are recently emerging as critical regulators of the c-Myc signaling pathway. Here, we report the lncRNA USP2-AS1 as a direct transcriptional target of c-Myc. Functionally, USP2-AS1 inhibits cellular senescence and acts as an oncogenic molecule by inducing E2F1 expression. Mechanistically, USP2-AS1 associates with the RNA-binding protein G3BP1 and facilitates the interaction of G3BP1 to E2F1 3'-untranslated region, thereby leading to the stabilization of E2F1 messenger RNA. Furthermore, USP2-AS1 is shown as a mediator of the oncogenic function of c-Myc via the regulation of E2F1. Together, these findings suggest that USP2-AS1 is a negative regulator of cellular senescence and also implicates USP2-AS1 as an important player in mediating c-Myc function.

The deubiquitinase USP38 promotes cell proliferation through stabilizing c-Myc.

The oncoprotein c-Myc is a master transcription factor that regulates the expression of a large number of genes involved in cell cycle, cell growth, and cell metabolism. Hence, it is important to keep the level of c-Myc under control. There are many proteins responsible for the degradation of c-Myc. However, the deubiquitinase-mediated stabilization of c-Myc remains less well understood. In this study, we found that USP38, an ubiquitin-specific protease, regulates the levels and function of c-Myc. USP38 can inhibit the polyubiquitination of c-Myc, thereby increasing c-Myc stability. Functionally, USP38 is able to promote cell proliferation via a c-Myc dependent manner. Mechanistically, USP38 physically interacts with FBW7α and abolishes FBW7α-mediated degradation of c-Myc. Furthermore, USP38 can restore the inhibitory effect of FBW7α on proliferation. Taken together, our study uncovers a novel role for USP38 in the regulation of c-Myc abundance and stability.

Upregulation of eukaryotic translation initiation factor 4E associates with a poor prognosis in gallbladder cancer and promotes cell proliferation in vitro and in vivo.

Eukaryotic translation initiation factor 4 (eIF4E) has been demonstrated to promote tumorigenesis in different types of cancer; however, whether eIF4E is involved in the development of GBC is unclear. The present study aimed to explore the biological function of eIF4E in gallbladder cancer (GBC) and identified that the expression level of eIF4E was significantly increased in GBC tissues compared with that in normal gallbladder tissues. The overall survival (OS) was also shorter in the group of patients with GBC with increased eIF4E expression. Increased eIF4E was correlated with advanced stage and higher histologic grade. Knockdown of eIF4E significantly inhibited cell proliferation, colony formation and cell cycle­associated protein expression levels in 2 GBC cell lines. The weight of the tumors in the eIF4E knockdown group was remarkably decreased compared with the control group. It also was revealed that knockdown of eIF4E is associated with upregulating cyclin­dependent kinase inhibitor 1B and downregulating the expression levels of cyclin E1 and cyclin D1 in vitro and in vivo. These data demonstrated that eIF4E is a novel prognostic marker in GBC and may serve a critical role in the regulation of cell proliferation.

Correlation of LARP1 and E-cadherin expression with prognosis of intrahepatic cholangiocarcinoma.

OBJECTIVE: The abnormal expression of LARP1 and E-cadherin (E-cad) is related to tumor occurrence and metastasis. Our study analyzed the expression of LARP1 and E-cad in intrahepatic cholangiocarcinoma (ICC) and investigated the prognostic value of the two proteins. METHODS: Immunohistochemistry was performed to detect the expression of LARP1 and E-cad in 50 ICC clinical specimens with adjacent normal tissues and 20 normal bile duct tissues. In situ hybridization was performed to analyze the expression of LARP1 mRNA in all the specimens. RESULTS: LARP1 protein and mRNA expression levels in ICC tumor tissues were significantly higher compared with corresponding adjacent normal tissues and normal epithelial tissues (P<0.01). E-cad protein expression in ICC tumor tissues was remarkably lower than that of the adjacent normal tissues and benign bile duct tissues (P<0.01). Correlation analysis demonstrated that LARP1 and E-cad expression levels were significantly related with the tumor-node-metastasis staging and lymph node metastasis (P<0.01), while no correlation was observed with patient age, gender, and tumor size. Moreover, Spearman rank correlation test revealed that LARP1 expression was negatively related to E-cad (P<0.05). More importantly, the patients with higher LARP1 expression or lower E-cad expression had a shorter overall survival postoperatively than those with LARP1 lower expression or E-cad higher expression. Multivariate analysis demonstrated that LARP1 and E-cad were both considered as important prognostic factors for survival time. CONCLUSION: These findings suggest that the abnormal expression of LARP1 and E-cad showed a close relationship with the occurrence and metastasis of ICC, leading to poor prognosis indirectly.