Assessment of arterial pulsatility of cerebral perforating arteries using 7T high-resolution dual-VENC phase-contrast MRI.

PURPOSE: Directly imaging the function of cerebral perforating arteries could provide valuable insight into the pathology of cerebral small vessel diseases (cSVD). Arterial pulsatility has been identified as a useful biomarker for assessing vascular dysfunction. In this study, we investigate the feasibility and reliability of using dual velocity encoding (VENC) phase-contrast MRI (PC-MRI) to measure the pulsatility of cerebral perforating arteries at 7 T. METHODS: Twenty participants, including 12 young volunteers and 8 elder adults, underwent high-resolution 2D PC-MRI scans with VENCs of 20 cm/s and 40 cm/s at 7T. The sensitivity of perforator detection and the reliability of pulsatility measurement of cerebral perforating arteries using dual-VENC PC-MRI were evaluated by comparison with the single-VENC data. The effects of temporal resolution in the PC-MRI acquisition and aging on the pulsatility measurements were investigated. RESULTS: Compared to the single VENCs, dual-VENC PC-MRI provided improved sensitivity of perforator detection and more reliable pulsatility measurements. Temporal resolution impacted the pulsatility measurements, as decreasing temporal resolution led to an underestimation of pulsatility. Elderly adults had elevated pulsatility in cerebral perforating arteries compared to young adults, but there was no difference in the number of detected perforators between the two age groups. CONCLUSION: Dual-VENC PC-MRI is a reliable imaging method for the assessment of pulsatility of cerebral perforating arteries, which could be useful as a potential imaging biomarker of aging and cSVD.

Design and characterization of a self-matching photonic lantern for all few-mode fiber laser systems.

We model and demonstrate a self-matching photonic lantern (SMPL) device, which is designed to address the constraint of limited transverse modes generated by fiber lasers. The SMPL incorporates a FMF into the array at the input end of a traditional photonic lantern. The few-mode fiber at the output end is specifically configured to align with the few-mode fiber at the input, therefore named as SMPL. This paper details the design and fabrication of the SMPL device, validated by both simulation and experiment. The 980nm fundamental mode, injected via 980nm single-mode fibers, selectively excites corresponding higher-order modes at the few-mode port of the SMPL. Additionally, 1550nm fundamental and higher-order modes injected at the input end into the SMPL device demonstrates mode preservation and low-loss transmission characteristics. The SMPL is well-suited for developing a ring laser system, enabling selective excitation of 980nm pump light modes and facilitating closed-loop oscillation and transmission of 1550nm laser.

USP8 promotes the tumorigenesis of intrahepatic cholangiocarcinoma via stabilizing OGT.

Ubiquitination was considered to be a crucial factor in intrahepatic cholangiocarcinoma (iCCA) development. Herein, we identified Ubiquitin-specific peptidase 8 (USP8) as a key regulator for promoting the tumorigenesis of iCCA cell via stabilizing OGT. USP8 was overexpressed in human tumor tissues and correlated with worse survival. Moreover, the mass spectrometry and co-immunoprecipitation analysis indicated that USP8 interacted with OGT. USP8 worked as a bona fide deubiquitylase of OGT. It stabilized OGT in a deubiquitylation activity-dependent manner. Meanwhile, DUB-IN3, the USP8 inhibitor, could also restrain the malignancy of intrahepatic cholangiocarcinoma. In addition, USP8 depletion promoted the response of iCCA to pemigatinib. In conclusion, our findings pointed to a previously undocumented catalytic role for USP8 as a deubiquitinating enzyme of OGT. The USP8-OGT axis could be a potential target for iCCA therapy.

Stabilization of estrogen receptor α by USP37 contributes to the progression of breast cancer.

Breast cancer is a major cause of cancer-related morbidity and mortality in women. Estrogen receptor-positive breast cancer accounts for roughly 70%-80% of breast tumors, and estrogen receptor alpha (ERα) has been considered as a key driver in promoting breast cancer progression. In the present study, we identified USP37 as a novel modulator in modulating ERα ubiquitination and stability. The expression of USP37 was upregulated in ERα-positive breast cancer and correlated with ERα protein level. High expression of USP37 was associated with unfavorable prognosis. USP37 depletion resulted in significantly decreased ERα protein level, ERα target genes expression as well as the estrogen response element activity in breast cancer cells. Further mechanistic study revealed the interaction between USP37 and ERα: USP37 regulated ERα signaling through modulating protein stability instead of gene expression, in which it stabilized ERα protein via inhibiting the K48-specific polyubiquitination process. Additionally, USP37 depletion led to growth inhibition and cell cycle arrest of ERα-positive breast cancer cells, which could be further rescued by ERα overexpression. Overall, our study proposed a novel post-translational mechanism of ERα in promoting breast cancer progression. Targeting USP37 may be proved to be a promising strategy for patients with ERα-positive breast cancer.

The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal human malignancies, and with quite limited treatment alternatives. The proteasome is responsible for most of the protein degradation in eukaryotic cells and required for the maintenance of intracellular homeostasis. However, its potential role in HCC is largely unknown. In the current study, we identified eukaryotic translation initiation factor 3 subunit H (EIF3H), belonging to the JAB1/MPN/MOV34 (JAMM) superfamily, as a bona fide deubiquitylase of O-GlcNAc transferase (OGT) in HCC. We explored that EIF3H was positively associated with OGT in HCC and was related to the unfavorable prognosis. EIF3H could interact with, deubiquitylate, and stabilize OGT in a deubiquitylase-dependent manner. Specifically, EIF3H was associated with the GT domain of ERα via its JAB/MP domain, thus inhibiting the K48-linked ubiquitin chain on OGT. Besides, we demonstrated that the knockdown of EIF3H significantly reduced OGT protein expression, cell proliferation and invasion, and caused G1/S arrest of HCC. We also found that the deletion of EIF3H prompted ferroptosis in HCC cells. Finally, the effects of EIF3H depletion could be reversed by further OGT overexpression, implying that the OGT status is indispensable for EIF3H function in HCC carcinogenesis. In summary, our study described the oncogenic function of EIF3H and revealed an interesting post-translational mechanism between EIF3H, OGT, and ferroptosis in HCC. Targeting the EIF3H may be a promising approach in HCC. Video Abstract.

ATXN3 promotes prostate cancer progression by stabilizing YAP.

BACKGROUND: Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. METHODS: Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. RESULTS: In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. CONCLUSIONS: In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. Video Abstract.

Advanced Fiber Sensors Based on the Vernier Effect.

For decades, optical fiber interferometers have been extensively studied and applied for their inherent advantages. With the rapid development of science and technology, fiber sensors with higher detection sensitivity are needed on many occasions. As an effective way to improve measurement sensitivity, Vernier effect fiber sensors have drawn great attention during the last decade. Similar to the Vernier caliper, the optical Vernier effect uses one interferometer as a fixed part of the Vernier scale and the other as a sliding part of the Vernier scale. This paper first illustrates the principle of the optical Vernier effect, then different configurations used to produce the Vernier effect are classified and discussed. Finally, the outlook for Vernier effect fiber sensors is presented.

MINDY1 promotes bladder cancer progression by stabilizing YAP.

BACKGROUND: Bladder cancer is one of the most commonly diagnosed urological malignant tumor. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in bladder cancer remains to be characterized. METHODS: Western blot was used to measure the expression of MINDY1 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect the cell viability. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between MINDY1 and YAP. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. RESULTS: In the present study, we identified MINDY1, a DUB enzyme in the motif interacting with ubiquitin-containing novel DUB family, as a bona fide deubiquitylase of YAP in bladder cancer. MINDY1 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. MINDY1 depletion significantly decreased bladder cancer cell proliferation. The effects induced by MINDY1 depletion could be rescued by further YAP overexpression. Depletion of MINDY1 decreased the YAP protein level and the expression of YAP/TEAD target genes in bladder cancer, including CTGF, ANKRD1 and CYR61. CONCLUSION: In general, our findings establish a previously undocumented catalytic role for MINDY1 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of bladder cancer.

A prognostic eight-lncRNA expression signature in predicting recurrence of ER-positive breast cancer receiving endocrine therapy.

Long noncoding RNAs (lncRNAs) have the main role in the tumorigenesis of breast cancer. In the present study, lncRNA expression profiling was collected to identify a lncRNA expression signature from the Gene Expression Omnibus database. An eight-lncRNA signature was established to predict the survival of patients with estrogen receptor (ER)-positive breast cancer receiving endocrine therapy. Patients were separated into a low-risk group and a high-risk group based on this signature. Patients in high-risk group have worse survival compared to those in low-risk group using Kaplan-Meier curve analysis with log-rank test. Receiver operating characteristic analysis suggested good diagnostic efficiency of the eight-lncRNA signature. When adjusting the clinical features, including age, grade, lymph node status, and tumor size, this signature was independently associated with the relapse-free survival. The prognostic value of the lncRNA prognostic model was then validated in validation sets. When validated in a cohort of patients treated with neoadjuvant chemotherapy and endocrine therapy, this signature demonstrated good performance as well. Besides, we have built a nomogram that integrated the conventional clinicopathological features and the eight-lncRNA-based signature. To sum up, our results indicated that the eight-lncRNA prognostic model was a reliable tool to group patients at high and low risk of disease relapse. This signature may have possible implication in prognostic evaluations of patients with ER-positive breast cancer receiving endocrine therapy.

Weighted gene correlation network analysis identifies RSAD2, HERC5, and CCL8 as prognostic candidates for breast cancer.

As the most commonly diagnosed malignant tumor in female population, the prognosis of breast cancer is affected by complex gene interaction networks. In this research weighted gene co-expression network analysis (WGCNA) would be utilized to build a gene co-expression network to identify potential biomarkers for prediction the prognosis of patients with breast cancer. We downloaded GSE25065 from Gene Expression Omnibus database as the test set. GSE25055 and GSE42568 were utilized to validate findings in the research. Seven modules were established in the GSE25065 by utilizing average link hierarchical clustering. Three hub genes, RSAD2, HERC5, and CCL8 were screened out from the significant module (R 2 = 0.44), which were considerably interrelated to worse prognosis. Within test dataset GSE25065, RSAD2, and CCL8 were correlated with tumor stage, grade, and lymph node metastases, whereas HERC5 was correlated with lymph node metastases and tumor grade. In the validation dataset GSE25055 and RSAD2 expression was correlated with tumor grade, stage, and size, whereas HERC5 was related to tumor stage and tumor grade, and CCL8 was associated with tumor size and tumor grade. Multivariable survival analysis demonstrated that RSAD2, HERC5, and CCL8 were independent risk factors. In conclusion, the WGCNA analysis conducted in this study screened out novel prognostic biomarkers of breast cancer. Meanwhile, further in vivo and in vitro studies are required to make the clear molecular mechanisms.

A prognostic eight-gene expression signature for patients with breast cancer receiving adjuvant chemotherapy.

Breast cancer is a popularly diagnosed malignant tumor. Genomic profiling studies suggest that breast cancer is a disease with heterogeneity. Chemotherapy is one of the chief means to treat breast cancer, while its responses and clinical outcomes vary largely due to the conventional clinicopathological factors and inherent chemosensitivity of breast cancer. Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, our study established a multi-mRNA-based signature model and constructed a relative nomogram in predicting distant-recurrence-free survival for patients receiving surgery and following chemotherapy. We constructed a signature of eight mRNAs (IPCEF1, SYNDIG1, TIGIT, SPESP1, C2CD4A, CLCA2, RLN2, and CCL19) with the LASSO model, which was employed to separate subjects into groups with high- and low-risk scores. Obvious differences of distant-recurrence-free survival were found between these two groups. This eight-mRNA-based signature was independently associated with the prognosis and had better prognostic value than classical clinicopathologic factors according to multivariate Cox regression results. Receiver operating characteristic results demonstrated excellent performance in diagnosing 3-year distant-recurrence by the eight-mRNA signature. A nomogram that combined both the eight-mRNA-based signature and clinicopathological risk factors was constructed. Comparing with an ideal model, the nomograms worked well both in the training and validation sets. Through the results that the eight-mRNA signature effectively classified patients into low- and high-risk of distant recurrence, we concluded that this eight-mRNA-based signature played a promising predictive role in prognosis and could be clinically applied in breast cancer patients receiving adjuvant chemotherapy.

An estrogen receptor (ER)-related signature in predicting prognosis of ER-positive breast cancer following endocrine treatment.

Quite a few estrogen receptor (ER)-positive breast cancer patients receiving endocrine therapy are at risk of disease recurrence and death. ER-related genes are involved in the progression and chemoresistance of breast cancer. In this study, we identified an ER-related gene signature that can predict the prognosis of ER-positive breast cancer patient receiving endocrine therapy. We collected RNA expression profiling from Gene Expression Omnibus database. An ER-related signature was developed to separate patients into high-risk and low-risk groups. Patients in the low-risk group had significantly better survival than those in the high-risk group. ROC analysis indicated that this signature exhibited good diagnostic efficiency for the 1-, 3- and 5-year disease-relapse events. Moreover, multivariate Cox regression analysis demonstrated that the ER-related signature was an independent risk factor when adjusting for several clinical signatures. The prognostic value of this signature was validated in the validation sets. In addition, a nomogram was built and the calibration plots analysis indicated the good performance of this nomogram. In conclusion, combining with ER status, our results demonstrated that the ER-related prognostic signature is a promising method for predicting the prognosis of ER-positive breast cancer patients receiving endocrine therapy.

A prognostic 10-lncRNA expression signature for predicting the risk of tumour recurrence in breast cancer patients.

Breast cancer is one of the most frequently diagnosed malignancies and a leading cause of cancer death among females. Multiple molecular alterations are observed in breast cancer. LncRNA transcripts were proved to play important roles in the biology of tumorigenesis. In this study, we aimed to identify lncRNA expression signature that can predict breast cancer patient survival. We developed a 10-lncRNA signature-based risk score which was used to separate patients into high-risk and low-risk groups. Patients in the low-risk group had significantly better survival than those in the high-risk group. Receiver operating characteristic analysis indicated that this signature exhibited excellent diagnostic efficiency for 1-, 3- and 5-year disease-relapse events. Moreover, multivariate Cox regression analysis demonstrated that this 10-lncRNA signature was an independent risk factor when adjusting for several clinical signatures such as age, tumour size and lymph node status. The prognostic value of risk scores was validated in the validation set. In addition, a nomogram was established and the calibration plots analysis indicated the good performance and clinical utility of the nomogram. In conclusion, our results demonstrated that this 10-lncRNA signature effectively grouped patients at low and high risk of disease recurrence.

Subtotal parathyroidectomy versus total parathyroidectomy with autotransplantation for secondary hyperparathyroidism: an updated systematic review and meta-analysis.

PURPOSE: The optimal surgical approach of parathyroidectomy for patients with secondary hyperparathyroidism (SHPT) has been controversial. The updated meta-analysis aimed to compare the effectiveness of subtotal parathyroidectomy (SPTX) versus total parathyroidectomy with autotransplantation (TPTX + AT). METHODS: A thorough systematic search was performed on the databases of PubMed, EMBASE, and Cochrane library to identify eligible studies. Data were extracted and pooled into a meta-analysis. The primary outcomes were the symptomatic improvement, radiological changes, hypocalcemia rate, the requirement for vitamin D analogues, time to recurrence, recurrence, persistence, and reoperation rates of SPTX versus TPTX + AT. RESULTS: A total of 18 studies with 3656 patients (1864 patients in SPTX and 1792 patients in TPTX + AT group) were included, and 15 studies were included in quantitative synthesis. No significant difference was observed in symptomatic improvement (93.3%, 89.0%; P = 0.99), radiological changes (85.4%, 85.3%; P = 0.91), hypocalcemia rate (16.6%, 18.1%; P = 0.29), persistence rate (6.1%, 2.0%; P = 0.16), time to recurrence (mean difference 1.46; P = 0.87), recurrence rate (9.2%, 7.1%; P = 0.76), and reoperation rate (5.3%, 5.8%; P = 0.66) between SPTX and TPTX + AT groups. Longer operative time (150 vs. 120 min), prolonged in-hospital stay (5.0 vs. 4.1 days), lower 1-month serum calcium level, and higher requirement for vitamin D analogues at 12 months were significantly observed in patients who underwent TPTX + AT compared to SPTX. CONCLUSIONS: The two surgical approaches were both effective at controlling SHPT in clinical and laboratory terms. However, most of the data shown were not statistically significant. It was acceptable that surgeons chose either SPTX or TPTX + AT for SHPT.

Racial disparities of differentiated thyroid carcinoma: clinical behavior, treatments, and long-term outcomes.

BACKGROUND: The incidence of thyroid cancer in black Americans is significantly lower than that in white Americans, and the impact of race on the prognosis of thyroid cancer remains controversial. The purpose of this study was to determine the risk factors for survival in black and white patients and to compare the survival of differentiated thyroid carcinoma subtypes between these two races. We further investigated the association of lymph node and distant metastases with races. METHODS: This is a retrospective analysis using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. A total of 70,346 cases were included in our study. Patients' demographics and cancer- and treatment-related characteristics were compared between the black and white Americans using chi-square and Fisher's exact tests. For multivariate analysis, Cox proportional hazards regression were used to assess the association between potential risk factors and the survival in black and white patients. RESULT: Black Americans had a worse overall survival than white Americans (HR = 1.127, P = 0.002). While disease-specific survival (DSS) was comparable, the risk factors for DSS were different between white and black Americans. Black Americans had less lymph node metastasis of classical variant papillary thyroid carcinoma (CPTC, OR = 0.476, P < 0.001) and follicular variant papillary thyroid carcinoma (FVPTC, OR = 0.522, P < 0.001), but not follicular thyroid carcinoma (FTC). However, black Americans with FVPTC, but not CPTC or FTC, had a higher potential of distant metastasis (OR = 1.715, P = 0.026). Furthermore, only white patients with tumor > 2 cm and lymph node metastasis benefited from radioactive iodine. CONCLUSIONS: The risk factors for DSS were significantly different in white and black patients. The impact of race should be considered in treatment strategy for thyroid cancer.

Identification and Validation of a Necroptosis-Related Prognostic Model in Tumor Recurrence and Tumor Immune Microenvironment in Breast Cancer Management.

Background: Breast cancer is the leading cause of cancer-related death in women. Necroptosis, a form of programmed necrotic cell death, occurs in many solid tumors, including breast cancer, and influences anti-tumor immunity. The role of necroptosis in managing breast cancer recurrence remains unclear. Methods: Gene expression profiles and clinical data of breast cancer patients were obtained from the GEO (GSE20685, GSE21653, GSE25055) and TCGA databases. Data analysis and visualization were performed using R. Unsupervised Consensus Clustering and LASSO-COX regression stratified breast cancer patients. GO, KEGG, GSVA, ESTIMATE, and ROC analyses were used to investigate necroptotic signatures. In vitro and in vivo experiments validated necroptosis's role in breast cancer immunity. Results: The potential function of necroptotic signature in immunity was first indicated with GO analysis in BRCA cohort. Next, two prognostic models based on the necroptotic profiles both suggested a link between low-risk group with a particular necroptotic immune signature. And a variety of immune cells and immune pathways were shown to be positively associated with a patient's risk score. As an altered immune checkpoint pattern was observed after regulating necroptotic genes, where TIM-3 and LAGLS9 elevated significantly in low-risk group, further validation in vitro and in vivo demonstrated that manipulating a subset of necroptotic gene set could sensitize tumor response to the co-blockade immunotherapy of anti-TIM-3 and anti-PD-1. Conclusion: We demonstrated two strategies to stratify breast cancer patients based on their necroptotic profiles and showed that necroptotic signature could assign patients with different tumor immune microenvironment patterns and different recurrence-related prognosis. A subset of necroptotic gene set, composed of TLR3, RIPK3, NLRP3, CASP1, ALDH2 and EZH2, was identified as a biomarker set for predicting immunotherapy-response and recurrence-related prognosis. Targeting necroptosis could helpfacilitate the development of novel breast cancer treatments and tailor personalized medical treatment.

Stimuli-Responsive Delivery Systems for Intervertebral Disc Degeneration.

As a major cause of low back pain, intervertebral disc degeneration is an increasingly prevalent chronic disease worldwide that leads to huge annual financial losses. The intervertebral disc consists of the inner nucleus pulposus, outer annulus fibrosus, and sandwiched cartilage endplates. All these factors collectively participate in maintaining the structure and physiological functions of the disc. During the unavoidable degeneration stage, the degenerated discs are surrounded by a harsh microenvironment characterized by acidic, oxidative, inflammatory, and chaotic cytokine expression. Loss of stem cell markers, imbalance of the extracellular matrix, increase in inflammation, sensory hyperinnervation, and vascularization have been considered as the reasons for the progression of intervertebral disc degeneration. The current treatment approaches include conservative therapy and surgery, both of which have drawbacks. Novel stimuli-responsive delivery systems are more promising future therapeutic options than traditional treatments. By combining bioactive agents with specially designed hydrogels, scaffolds, microspheres, and nanoparticles, novel stimuli-responsive delivery systems can realize the targeted and sustained release of drugs, which can both reduce systematic adverse effects and maximize therapeutic efficacy. Trigger factors are categorized into internal (pH, reactive oxygen species, enzymes, etc.) and external stimuli (photo, ultrasound, magnetic, etc.) based on their intrinsic properties. This review systematically summarizes novel stimuli-responsive delivery systems for intervertebral disc degeneration, shedding new light on intervertebral disc therapy.

UCHL3 inhibits ferroptosis by stabilizing ß-catenin and maintains stem-like properties of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic liver cancer. Dysregulated Wnt/ß-catenin activation is closely related to the progression of cancer. Nevertheless, the mechanism that sustains the abnormal expression of ß-catenin in HCC has yet to be identified. In this study, we find that UCHL3 is overexpressed in HCC tissues and correlated with ß-catenin protein level. High expression of UCHL3 is associated with poor prognosis. UCHL3 knockdown markedly reduces the protein level of ß-catenin in HCC cells. TOP-luciferase activity and ß-catenin target genes expression are also decreased upon UCHL3 depletion. We find that the ARM domain of ß-catenin is required for the interaction with UCHL3. UCHL3 increases ß-catenin protein stability via removing K48-specific poly-ubiquitin chains from ß-catenin protein. Furthermore, the depletion of UCHL3 induces ferroptosis and hinders the growth, invasion, and stem cell properties of HCC cells. These impacts could be restored by the overexpression of ß-catenin. In addition, the UCHL3 inhibitor TCID inhibits the aggressive phenotype of HCC through the degradation of ß-catenin. In general, our results indicates that UCHL3 increases the stability of ß-catenin, which in turn facilitates tumorigenesis of HCC, suggesting that targeting UCHL3 may be a promising approach for the treatment of HCC.

Histones Methyltransferase NSD3 Inhibits Lung Adenocarcinoma Glycolysis Through Interacting with PPP1CB to Decrease STAT3 Signaling Pathway.

Histones methyltransferase NSD3 targeting H3K36 is frequently disordered and mutant in various cancers, while the function of NSD3 during cancer initiation and progression remains unclear. In this study, it is proved that downregulated level of NSD3 is linked to clinical features and poor survival in lung adenocarcinoma. In vivo, NSD3 inhibited the proliferation, immigration, and invasion ability of lung adenocarcinoma. Meanwhile, NSD3 suppressed glycolysis by inhibiting HK2 translation, transcription, glucose uptake, and lactate production in lung adenocarcinoma. Mechanistically, as an intermediary, NSD3 binds to PPP1CB and p-STAT3 in protein levels, thus forming a trimer to dephosphorylate the level of p-STAT3 by PPP1CB, leading to the suppression of HK2 transcription. Interestingly, the phosphorylation function of PPP1CB is related to the concentration of carbon dioxide and pH value in the culture environment. Together, this study revealed the critical non-epigenetic role of NSD3 in the regulation of STAT3-dependent glycolysis, providing a piece of compelling evidence for targeting the NSD3/PPP1CB/p-STAT3 in lung adenocarcinoma.

USP8 positively regulates hepatocellular carcinoma tumorigenesis and confers ferroptosis resistance through ß-catenin stabilization.

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic carcinoma, which is a growing public health problem worldwide. One of the main genetic alterations in HCC is the deregulated Wnt/ß-catenin signaling, activation of ß-catenin is associated with the progression of HCC. In the present study, we aimed to identify novel modulators in controlling ß-catenin ubiquitination and stability. USP8 was overexpressed in HCC tissues and correlated with ß-catenin protein level. High expression of USP8 indicated poor prognosis of HCC patients. USP8 depletion significantly decreased ß-catenin protein level, ß-catenin target genes expression and TOP-luciferase activity in HCC cells. Further mechanistic study revealed that the USP domain of USP8 interacted with the ARM domain of ß-catenin. USP8 stabilized ß-catenin protein via inhibiting K48-specific poly-ubiquitination process on ß-catenin protein. In addition, USP8 depletion inhibited the proliferation, invasion and stemness of HCC cells and conferred ferroptosis resistance, which effects could be further rescued by ß-catenin overexpression. In addition, the USP8 inhibitor DUB-IN-3 inhibited the aggressive phenotype and promoted ferroptosis of HCC cells through degradation of ß-catenin. Thus, our study demonstrated that USP8 activated the Wnt/beta-catenin signaling through a post-translational mechanism of ß-catenin. High expression of USP8 promoted the progression and inhibited ferroptosis of HCC. Targeting the USP8 may serve as a promising strategy for patients with HCC.