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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. [ABSTRACT FROM AUTHOR]

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

Background: Laparoscopic major liver resection, such as laparoscopic left hemihepatectomy (LLH), is still perceived as a complicated procedure due to technical difficulties and slow learning curve. The study introduced an optimized procedure using the liver parenchyma transection-first approach and investigated its advantages on surgical outcomes by comparison with the conventional hilar dissection approach for LLH. Methods: Between January 2015 and May 2019, 96 patients who underwent laparoscopic left hemihepatectomy for hepatocellular carcinoma (HCC) were enrolled in the study. Among these, 41 patients underwent the liver parenchyma transection-first approach (LP-first group) and the other 55 underwent the conventional hilar dissection approach (conventional group). A 1:1 propensity score matching (PSM) was performed to compare the perioperative and long-term oncological outcomes of the two groups. Results: After 1:1 PSM, 37 patients in each group were selected for further analysis. The LP-first group was associated with shorter median operative time (210 vs 235 min, P = 0.035) and less blood loss (200 vs 300 mL, P = 0.410). In addition, no statistical differences were found in overall complications between the two groups (8.1% vs 24.3%, P = 0.058). There were no significant differences between the two groups in terms of 1-year and 3-year disease-free survival (DFS, P = 0.608) and overall survival (OS, P = 0.414). Conclusion: The prior liver parenchyma approach for LLH is safe and reproducible in selected patients, which showed improved perioperative outcomes and comparable long-term oncological outcomes compared with the conventional approach. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti‐tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB‐IN‐3 shows the most effective anti‐cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB‐IN‐3 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O‐GlcNAc transferase (OGT) via inhibiting K48‐specific poly‐ubiquitination process on OGT protein at K117 site, and STE20‐like kinase (SLK)‐mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O‐GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. Collectively, this study demonstrates that pharmacological inhibition or knockout of USP8 can inhibit the progression of HCC and induce ferroptosis via decreasing the stability of OGT, which imposes a great challenge that targeting of USP8 is a potential approach for HCC treatment. [ABSTRACT FROM AUTHOR]

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. 6aJiHquPswT5dhvMxQLovC Video Abstract [ABSTRACT FROM AUTHOR]

BRCA1 interacting helicase 1 (BRIP1) alteration was crucial in tumors and it was a potential therapeutic target in ovarian serous cystadenocarcinoma (OV). Although a small number of studies had focused on BRIP1, an extensive study of BRIP1 genetic mutation and its clinical application in different cancer types had not been analyzed. In the current study, we analyzed BRIP1 abnormal expression, methylation, mutation, and their clinical application via several extensive datasets, which covered over 10,000 tumor samples across more than 30 cancer types. The total mutation rate of BRIP1 was rare in pan cancer. Its alteration frequency, oncogenic effects, mutation, and therapeutic implications were different in each cancer. 242 BRIP1 mutations were found across 32 cancer types. UCEC had the highest alteration (mutation and CNV) frequency. In addition, BRIP1 was a crucial oncogenic factor in OV and BRCA. BRIP1 mutation in PRAD was targetable, and FDA had approved a new drug. Moreover, Kaplan–Meier curve analysis showed that BRIP1 expression and genetic aberrations were closely related to patient survival in several cancers, indicating their potential for application as new tumor markers and therapeutic targets. The current study profiled the total BRIP1 mutation spectrum and offered an extensive molecular outlook of BRIP1 in a pan cancer analysis. And it suggested a brand-new perspective for clinical cancer therapy. [ABSTRACT FROM AUTHOR]

Introduction: Systemic nutrition and inflammation are the critical factors in cancer initiation, evolution, and progression. This study aimed to evaluate the prognostic value of the prognostic nutritional index (PNI) and systemic immune-inflammation index (SII) in hepatocellular carcinoma (HCC) patients who underwent liver resection. Methods: A total of 202 HCC patients met the criteria and were included in the study. The receiver operating characteristic (ROC) curve was used to calculate the optimal PNI and SII cutoff values. The relationship between PNI/SII and clinicopathologic parameters was analyzed. The effect of PNI and SII on recurrence-free survival (RFS) and overall survival (OS) was investigated by Kaplan-Meier curves and Cox proportional hazards models. Results: The areas under the ROC curve for PNI and SII were 0.64 and 0.58. The ideal preoperative PNI and SII cutoff values were 50.25 and 461.5, respectively. Multivariate Cox regression analysis identified that the PNI (P = 0.001) and tumor diameter (P = 0.018) were significant prognostic markers for RFS, and that the PNI (P = 0.049), SII (P = 0.039) and tumor diameter (P = 0.001) were significant prognostic markers for OS. The median RFS in the PNI-low and PNI-high groups was 13.5 months and 23 months (P = 0.001), and that in the SII-low and SII-high groups was 18 months and 15 months (P = 0.03), respectively. The median OS in the PNI-low and PNI-high groups was 24 months and 39 months (P = 0.001), and that in the SII-low and SII-high groups was 36 months and 22 months (P = 0.002), respectively. Conclusion: Interestingly, we found that PNI and SII could be important prognostic parameters for HCC patients who under hepatectomy. [ABSTRACT FROM AUTHOR]

Tumor biomarkers are eagerly needed in monitoring the recurrence of operable hepatocellular carcinoma (HCC). Circulating cell-free DNA (cfDNA) is a promising noninvasive molecular biomarker for HCC. The current study aimed to evaluate the clinical significance of the postoperative cfDNA in operable HCC. This study enrolled 82 HCC patients from January 2018 to June 2019. All patients underwent liver surgery and were pathologically diagnosed with HCC. Postoperative blood samples were collected from each patient. A fluorometric dsDNA assay was used to measure the concentration of cfDNA. We explore the correlation between cfDNA and recurrence. Kaplan–Meier's curves were used to evaluate the recurrence-free survival (RFS). Univariate and multivariate Cox regression analyses were used for assessing the relative clinical variables in predicting recurrence. Of the 82 HCC patients, 72 (87%) patients are male and the average age was 52.7 ± 12.8 years. The cfDNA-low and cfDNA-high groups had median recurrence times of 19.5 months and 14.0 months, respectively (p =.023). Multivariate analysis showed that postoperative cfDNA, tumour number and microvascular invasion (p <.050) were independent risk factors for recurrence in operable HCC. Postoperative cfDNA is still a promising marker to predict prognosis in postoperative HCC patients although prospective and large multicenter clinical study is needed to further validate the relationship between cfDNA and HCC recurrence. [ABSTRACT FROM AUTHOR]

Background & Aims: Microvascular invasion (MVI) is a critical prognostic factor for operable hepatocellular carcinoma (HCC). This study aimed to explore the performance of circulating tumour DNA (ctDNA) in evaluating MVI status preoperatively. Methods: Seventy‐three HCC patients were enrolled and randomly divided into a training cohort and a validation cohort in a 2:1 ratio, and preoperative blood and surgical tissue samples were obtained. Genomic alterations were analysed using targeted deep sequencing with a 1021‐gene panel. Results: In training cohort, 260 somatic mutations were identified in 40 blood samples (81.6%). CtDNA mutation was verified in paired tissue sample in 39 patients (97.5%). In univariate analysis, ctDNA allele frequency (AF) and largest tumour diameter were associated with the presence of MVI, but ctDNA AF was the only independent risk factor in multivariate analysis. With the cut‐off value of 0.83%, ctDNA AF determined the presence of MVI with the sensitivity of 89.7% and specificity of 80.0% in the training cohort, and the sensitivity of 78.6% and the specificity of 81.8% in the validation cohort. In preoperative evaluation, ctDNA AF, AFP level and BCLC staging were associated with recurrence‐free survival in both univariate and multivariate analysis. Conclusions: CtDNA can serve as an independent risk factor of MVI for operable HCC and help determining precise treatment strategies. The integration of ctDNA in the management of operable HCC may achieve better clinical outcomes. [ABSTRACT FROM AUTHOR]

Sensitive detection of cancer cells is beneficial to the early diagnosis of cancer and individual treatment. In the present study, a DNA nanostructured aptasensor was used for the sensitive electrochemical detection of human liver hepatocellular carcinoma cells (HepG2) based on multibranched hybridization chain reaction amplification strategy. We established a well-designed platform by immobilizing DNA tetrahedron, a three-dimensional DNA nanostructure, on the gold electrode to capture HepG2 cells more specifically and efficiently. Meanwhile, functional hybrid nanoprobes consisted of MIL-101@AuNPs (Au nanoparticles), numerous hemin/G-quadruplex DNAzyme from multibranched hybridization chain reaction, and natural horseradish peroxidase (HRP) was designed. The hybrid nanoprobes possessed the functions of specific discernment and enzymatic signal amplification simultaneously. With the help of nanoprobes, HepG2 cells were recognized and captured to form a DNA tetrahedron-cell-nanoprobe sandwich-like structure on the electrode surface. The lower detection limit of this established cytosensor is 5 cells per ml. Moreover, it delivered a broad detection range from 10 2 to 10 7 cells per ml. The results revealed that the as-proposed cytosensor may be utilized as a powerful tool for early diagnosis of cancer in the future. [ABSTRACT FROM AUTHOR]

We are very pleased that our research has received peer attention and comments,1 which also emphasized the importance of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). The proportion of patients with macrovascular invasion was 10.20%, but in tumours less than 2 cm, the MVI was only present in 2.04% (1/49). Besides, 15 had MVI (40.5%, 15/37) with the size of the tumour of less than 2 cm. Nonetheless, overall analysis showed that the incidence of MVI with tumours of less than 2cm was 4.66% (15/322). [Extracted from the article]

• Three-dimensional DNA tetrahedron was utilized for the highly enhanced capture of breast cancer biomarker HER2. • The bioconjugate of GNR@Pd SSs—Apt—HRP together amplified the electrochemical signals significantly. • This biosensor exhibited a high detection specificity and sensitivity with a lower detection limit (0.15 ng mL-1) for HER2. Sensitive and accurate detection of human epidermal growth factor receptor 2 (HER2) can contribute to the clinical diagnosis and individual treatment of breast cancer. In this work, a DNA nanostructured biosensor was developed for electrochemical analysis of HER2 sensitively using the bioconjugate of gold nanorod@Pd superstructures—aptamer—horseradish peroxidase (GNR@Pd SSs—Apt—HRP) as the signal probe to realize signal amplification. We constructed a biosensing interface by immobilizing DNA tetrahedron with expanded aptamer, on the gold electrode to detect HER2 more efficiently and specifically. Besides, signal nanoprobe consisted of GNR@Pd SSs, aptamer and natural HRP was designed. The bioconjugate of GNR@Pd SSs—Apt—HRP was equipped with the functions of recognition with specificity and signal amplification based on enzymatic catalysis simultaneously. In virtue of aptamer, HER2 was discerned and caught to establish a DNA tetrahedron-HER2-nanoprobes sandwich-type structure on gold electrode surface. The developed biosensor exhibited limit of detection as low as 0.15 ng mL−1 toward HER2. Meanwhile, it delivered a wide range of linearity from 10 to 200 ng mL−1. The results prove that this proposed biosensor have the applicability and potential to develop powerful diagnostic tools for breast cancer in the future. [ABSTRACT FROM AUTHOR]

Efforts have been taken to enhance the study of single‐cells, however, the task remains challenging because most previous investigations cannot exclude the interactions between single cells or separately retrieved cells with specificity for further analyses. Here, a single‐cell mobility analysis platform (SCM‐Chip) is developed that can not only real‐time monitor single‐cell migration in independent niches but can also selectively recover target cells one by one. The design of each channel with a single‐cell capture unit and an outlet enables the system to place single cells in different isolated niches with fluidic capture and to respectively collect target cells based on mobilities. SCM‐Chip characterization of breast cancer cells reveals the presence of high‐ and low‐migratory populations. Whole‐cell transcriptome analysis establishes that monocyte chemotactic protein induced protein 1 (MCPIP1) is related with cell mobility; cells with a high expression of MCPIP1 exhibit low mobility in vitro and metastasis in vivo. The SCM platform provides a generic tool for accurate single‐cell isolation and differentiation that can be readily adapted for the study of cancer and drug development. A single‐cell mobility chip is developed to separate cells based on mobility with the capability of single‐cell capture, migration monitoring, retrieval, and RNA‐sequencing. This platform could serve as a useful tool in discovering novel mediators of cell migration. [ABSTRACT FROM AUTHOR]

The extensive phenotypic and functional heterogeneity of cancer cells plays an important role in tumor progression and therapeutic resistance. Characterizing this heterogeneity and identifying invasive phenotype may provide possibility to improve chemotherapy treatment. By mimicking cancer cell perfusion through circulatory system in metastasis, we develop a unique microfluidic cytometry (MC) platform to separate cancer cells at high throughput, and further derive a physical parameter 'transportability' to characterize the ability to pass through micro-constrictions. The transportability is determined by cell stiffness and cell-surface frictional property, and can be used to probe tumor heterogeneity, discriminate more invasive phenotypes and correlate with biomarker expressions in breast cancer cells. Decreased cell stiffness and cell-surface frictional force leads to an increase in transportability and may be a feature of invasive cancer cells by promoting cell perfusion through narrow spaces in circulatory system. The MC-Chip provides a promising microfluidic platform for studying cell mechanics and transportability could be used as a novel marker for probing tumor heterogeneity and determining invasive phenotypes. [ABSTRACT FROM AUTHOR]