Retrospective analysis of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), Ki67 changes and their clinical significance between primary breast cancer and metastatic tumors.

Objective: To explore the relationship between receptor heterogeneity and clinicopathological characteristics in 166 patients with invasive breast cancer during metastasis. Methods: We conducted a retrospective analysis of 166 patients diagnosed with metastatic breast cancer through biopsy, who were admitted to our hospital from January 2018 to December 2022. Statistical analysis was employed to assess the heterogeneity of receptors in both primary and metastatic lesions, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), Ki67, as well as their association with clinicopathological features such as tumor size, lymph node metastasis, treatment regimen, and disease-free survival. Results: The discordant expression rates of ER, PR, HER2, Ki-67 and Luminal classification between primary and metastatic lesions were 21.7%, 41.6%, 8.9%, 34.4% and 36.8%, respectively. There is a significant difference in disease-free survival between patients with consistent and inconsistent receptor status of primary and metastatic lesions, which is statistically significant. The median DFS for primary HER2(-) to metastatic HER2(+) was 84 months, which was relatively high. The Cox multivariate regression analysis revealed that the expression differences of ER, PR, HER2, and Ki67 were not influenced by endocrine therapy and chemotherapy. However, a statistically significant difference in HER2 expression was observed with targeted therapy. Tumor size was correlated with ER and Ki67 receptor status (P = 0.019, 0.016). Tumor size was not correlated with PR, and HER2 (P = 0.679, 0.440). Lymph node metastasis was not associated with changes in ER, PR, HER2, and Ki67. The discordant rates of ER, PR, HER2, and Ki-67 in patients with local recurrence were 22%, 23.7%, 5.1%, and 28.8% respectively, whereas those in patients with distant metastasis were 21.5%, 36.4%, 10.3%, and 31.8% respectively. Conclusions: The expression levels of ER, PR, HER2, and Ki-67 in primary and metastatic breast cancer exhibit heterogeneity, which is closely associated with the prognosis and treatment outcomes of patients.

A prediction model based on digital breast pathology image information.

BACKGROUND: The workload of breast cancer pathological diagnosis is very heavy. The purpose of this study is to establish a nomogram model based on pathological images to predict the benign and malignant nature of breast diseases and to validate its predictive performance. METHODS: In retrospect, a total of 2,723 H&E-stained pathological images were collected from 1,474 patients at Qingdao Central Hospital between 2019 and 2022. The dataset consisted of 509 benign tumor images (adenosis and fibroadenoma) and 2,214 malignant tumor images (infiltrating ductal carcinoma). The images were divided into a training set (1,907) and a validation set (816). Python3.7 was used to extract the values of the R channel, G channel, B channel, and one-dimensional information entropy from all images. Multivariable logistic regression was used to select variables and establish the breast tissue pathological image prediction model. RESULTS: The R channel value, B channel value, and one-dimensional information entropy of the images were identified as independent predictive factors for the classification of benign and malignant pathological images (P < 0.05). The area under the curve (AUC) of the nomogram model in the training set was 0.889 (95% CI: 0.869, 0.909), and the AUC in the validation set was 0.838 (95% CI: 0.7980.877). The calibration curve results showed that the calibration curve of this nomogram model was close to the ideal curve. The decision curve results indicated that the predictive model curve had a high value for auxiliary diagnosis. CONCLUSION: The nomogram model for the prediction of benign and malignant breast diseases based on pathological images demonstrates good predictive performance. This model can assist in the diagnosis of breast tissue pathological images.

Investigation of Mold Flux Entrapment in Deep Oscillation Mark of Interstitial-Free Steel Shell Using Mold Simulator.

The slag entrapment defect has become a big issue for the IF steel casting process. In this study, the mechanism of mold flux entrapment in deep oscillation mark of an IF steel shell was studied by a high-temperature mold simulator. Results show that both temperature and heat flux in a copper mold become lower when mold flux B with lower melting and viscosity is used, compared with these when mold flux A with higher melting and viscosity is used. The average thickness of the slag film for mold fluxes A and B is 1.31 mm and 1.63 mm, and the consumption of them is 0.33 kg/m2 and 0.35 kg/m2, respectively. The shell for mold flux A exhibits sharper oscillation marks, while the shell for mold flux B has shallower oscillation marks. These deeper oscillation marks capture the mold flux by overflow of molten steel at the meniscus, which finally produces the slag entrapment defect in the shell.

Health risk assessment and potential sources of metals in riparian soils of the Wujiang River, China.

In order to understand the pollution status of metals in the riparian soils along the Wujiang River, 26 sampling sites in the mainstream and tributary streams were selected for investigation. The geo-accumulation index (Igeo), Nemerow integrated pollution index, and potential ecological risk index were applied to evaluate the contamination status and ecological risks of metals. Results revealed that the average concentrations of As, Cd, Cr, Cu, Mn, Ni, Pb, and Zn were 12.20, 0.51, 84.01, 57.42, 922.57, 38.37, 38.06, and 127.82 mg/kg, respectively. The metal contamination degree and ecological risks in the upper reaches were significantly higher than those in the middle and lower reaches of the Wujiang River. Cd was the dominant contamination metal. Significant non-carcinogenic and carcinogenic risks of metals were found in children based on the hazard index and carcinogenic risk. As was the main non-carcinogenic and carcinogenic pollutant metal in both adults and children. According to principal component analysis, hierarchical clustering analysis, and absolute principal component scores-multiple linear regression, anthropogenic sources (mining and agricultural activities) contributed most to Zn, Pb, Cr, Cd, Cu, and Ni, with contribution rates of 89.14, 82.32, 74.46, 72.12, 68.52, and 61.02%, respectively. Natural sources contributed most to Mn, with a contribution rate of 83.07%. Unidentified sources contributed most to As, with a contribution rate of 47.27%.

Color restoration based on digital pathology image.

OBJECTIVE: Protective color restoration of faded digital pathology images based on color transfer algorithm. METHODS: Twenty fresh tissue samples of invasive breast cancer from the pathology department of Qingdao Central Hospital in 2021 were screened. After HE staining, HE stained sections were irradiated with sunlight to simulate natural fading, and every 7 days was a fading cycle, and a total of 8 cycles were experienced. At the end of each cycle, the sections were digitally scanned to retain clear images, and the color changes of the sections during the fading process were recorded. The color transfer algorithm was applied to restore the color of the faded images; Adobe Lightroom Classic software presented the histogram of the image color distribution; UNet++ cell recognition segmentation model was used to identify the color restored images; Natural Image Quality Evaluator (NIQE), Information Entropy (Entropy), and Average Gradient (AG) were applied to evaluate the quality of the restored images. RESULTS: The restored image color met the diagnostic needs of pathologists. Compared with the faded images, the NIQE value decreased (P<0.05), Entropy value increased (P<0.01), and AG value increased (P<0.01). The cell recognition rate of the restored image was significantly improved. CONCLUSION: The color transfer algorithm can effectively repair faded pathology images, restore the color contrast between nucleus and cytoplasm, improve the image quality, meet the diagnostic needs and improve the cell recognition rate of the deep learning model.

Bioaccumulation and Health Risk Assessment of Metals in Small-Sized Fish (Rhodeus sinensis, Ctenogobius giurinus) and Mussel (Cristaria plicata) from a River Reservoir, Southwest China.

In order to assess the bioaccumulation and health risk of metals in a river reservoir, concentrations of copper (Cu), zinc (Zn), lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) in the water, sediments, two small-sized fish, and a freshwater mussel from the Zhoubai reservoir were examined. The results indicated that all of these metals conform with class one of environmental quality standards for surface water (State Environmental Protection Administration of China, GB 3838-2002). There were no significant differences for total metal concentrations in sediment between the three sampling sites (p > 0.05), but the bioavailable concentrations in S3 were the lowest. The Cd was dominated with exchangeable fraction and showed considerable risk. All metal concentrations except for Pb in Rhodeus sinensis were significantly higher than those in Ctenogobius giurinus (p < 0.05). The metal concentrations in Cristaria plicata showed a similar pattern of bioavailable metals in sediment, indicating that the metal concentrations in aquatic organisms were determined by the bioavailable forms of metals. Negative correlations were observed between the size of fish and concentrations of Cu, Zn, Pb, Cd, and As. However, significant positive correlations were found between the size of mussel and concentrations of Cd (p < 0.01), As (p < 0.05), and Hg (p < 0.01). Zn had the highest BCF values in fish and mussel. The aquatic organisms showed lower ability of metal bioaccumulation from the sediment. Low values of target hazard quotient (THQ), hazard index (HI), and carcinogenic risk (CR) indicated that these metals do not pose a health risk to public through fish and mussel consumption in this study area.

Comparative study on metal concentrations in water, sediments, and two fish species (Cyprinus carpio and Pelteobagrus fulvidraco) from the Wujiang River, China.

In order to assess the metal pollution in the Wujiang River, concentrations of Cu, Zn, Fe, Mn, Pb, Cd, As, and Hg in the water, sediments, and two fish species Cyprinus carpio and Pelteobagrus fulvidraco from the middle reaches (Tuomugang, TMG) and lower reaches (Wulong, WL) of the Wujiang River were examined. The results indicated that all metal concentrations were lower than the values for grade one water quality according to the Environment Quality Standard for Surface Water of China (GB 3838-2002). The bioavailable fraction concentrations of Zn, Fe, Mn, Pb, and Hg in WL were significantly higher than those in TMG (p < 0.05), indicating that these metals in sediments of WL have higher bioavailability and mobility. The Cu, Zn, Fe, Pb, As, and Hg were mainly related to the residual fraction, while the Mn and Cd were mainly associated with the non-residual fraction. The risk assessment code (RAC) and the secondary phase to the primary phase (RSP) values indicated that Mn and Cd have a high risk of secondary release. The mean metal concentrations in the liver of the two fish species were higher than those in muscle. The higher metal concentrations of fish in WL suggested that bioaccumulation of metals in fish could be influenced by metal bioavailability. No identical relationships between metal concentrations and fish length were manifested in the present study. The values of target hazard quotient (THQ) and hazard index (HI), and carcinogenic risk (CR) of metals for the consumption of C. carpio and P. fulvidraco indicated that the anglers would likely not experience significant non-carcinogenic risk, but the carcinogenic risk of As cannot be ignored. Thanks to prohibited commercial fishing in the Wujiang River, the metal pollution will probably not pose a health risk to the general public for wild fish consumption.

A clinical observational study on the application of enhanced recovery after laparoscopic pancreaticoduodenectomy.

Purpose: The safety and feasibility of enhanced recovery after surgery (ERAS) for laparoscopic pancreaticoduodenectomy (LPD) are unclear. The aim of this retrospective clinical study was to evaluate the impact of ERAS protocols for LPD. Patients and methods: Between March 2016 and December 2018, a total of 34 consecutive patients with ERAS for LPD were prospectively enrolled and compared with 68 consecutive patients previously treated for non-ERAS after LPD during an equal time frame. The intraoperative and postoperative data were collected and comparatively analyzed. Results: The mean length of postoperative hospital stay (15.8 ± 3.4 and 23.1 ± 5.1 days, P < 0.001) was reduced significantly in ER group than those in non-ER group. The operation time (462.7 ± 117.0 vs. 450.9 ± 109.8 min, P = 0.627) and intraoperative blood loss (523.5 ± 270.0 vs. 537.5 ± 241.8 ml, P = 0.800) were similar in the two groups. The complications (ER: 32.4% vs. non-ER: 35.3%, P > 0.05) and their severities (Clavien-Dindo grade ≥3 complications, 2 vs. 5 patients; P = 0.783) of patients with ERAS protocols were not increased. No difference in mortality and readmission rates was found. Finally, the total medical costs ($2.1 ± 0.7 × 104 and $2.3 ± 0.7 × 104, P = 0.017) in ER group were lower than those in non-ER group. Conclusion: the ERAS is safe and effective in the perioperative period of LPD. It could effectively reduce the length of postoperative stay and medical costs, and does not increase the incidence of postoperative complications.

Self-Healing Hydrogel Embodied with Macrophage-Regulation and Responsive-Gene-Silencing Properties for Synergistic Prevention of Peritendinous Adhesion.

Antiadhesion barriers such as films and hydrogels used to wrap repaired tendons are important for preventing the formation of adhesion tissue after tendon surgery. However, sliding of the tendon can compress the adjacent hydrogel barrier and cause it to rupture, which may then lead to unexpected inflammation. Here, a self-healing and deformable hyaluronic acid (HA) hydrogel is constructed as a peritendinous antiadhesion barrier. Matrix metalloproteinase-2 (MMP-2)-degradable gelatin-methacryloyl (GelMA) microspheres (MSs) encapsulated with Smad3-siRNA nanoparticles are entrapped within the HA hydrogel to inhibit fibroblast proliferation and prevent peritendinous adhesion. GelMA MSs are responsively degraded by upregulation of MMP-2, achieving on-demand release of siRNA nanoparticles. Silencing effect of Smad3-siRNA nanoparticles is around 75% toward targeted gene. Furthermore, the self-healing hydrogel shows relatively attenuated inflammation compared to non-healing hydrogel. The mean adhesion scores of composite barrier group are 1.67 ± 0.51 and 2.17 ± 0.75 by macroscopic and histological evaluation, respectively. The proposed self-healing hydrogel antiadhesion barrier with MMP-2-responsive drug release behavior is highly effective for decreasing inflammation and inhibiting tendon adhesion. Therefore, this research provides a new strategy for the development of safe and effective antiadhesion barriers.

Deep mining and quantification of oxidized cholesteryl esters discovers potential biomarkers involved in breast cancer by liquid chromatography-mass spectrometry.

Oxidized cholesteryl ester (OxCE) is produced by the oxidation of cholesteryl ester (CE) in the cores of lipoproteins. OxCE production and oxidative stress have been largely associated with breast cancer. Herein, we developed a novel reverse-phase liquid chromatography coupling quadrupole time-of-flight mass spectrometry (RPLC‒Q-TOF‒MS) method based on the iterative acquisition mode and used the MS/MS mode for deep mining and simultaneous quantification of cholesterol (Chol), CEs and OxCEs in human serum. A mathematical model was used to globally profile 57 molecular species of both CEs and OxCEs in the serum of both healthy volunteers and patients with breast cancer, and the qualitative results were verified based on the retention regularity. An abnormal elevation of OxCEs was found in serum samples of breast cancer patients, where OxCEs were produced by the oxidation of the fatty acyl chain of CE (20:4), such as CE (20:1)+3O, CE (20:2)+2O and CE (20:3)+O, which could be regarded as biomarkers. This comprehensive method for the global profiling of Chol, OxCEs and CEs sheds light on the role OxCEs and CEs play in breast cancer and has enabled the discovery of breast cancer biomarkers.

Mechanical and Acoustic Properties of Jute Fiber-Reinforced Polypropylene Composites.

Chemical fibers such as glass fiber and aramid cover a large proportion of sound-absorbing composite materials on the current commercial market. These materials possess superior mechanical properties but have the disadvantages of high production costs and energy consumption and difficult recovery and degradation. In this paper, jute fiber and polypropylene were selected as raw materials, and a series of jute fiber-reinforced polypropylene composite materials were prepared by a mixing-hot-pressing process. The acoustic and mechanical performances of the composites with different fiber contents and fiber residue ratios were discussed. The results showed that the sound absorption coefficient values increased with the increasing fiber content and decreasing residual gum ratio. The mechanical properties varied inversely with the residual gum rate. With the increase of fiber content, the tensile and bending strengths first increased and then decreased. Therefore, the jute fiber-reinforced polypropylene composites can possess favorable sound absorption performance with no mechanical property penalty by adjusting the parameters properly, demonstrating that the composite materials have promising applications in the acoustic field.

Surgical Resection of Pancreatic Hepatoid Carcinoma Followed by Combined Transarterial Chemoembolization and Immunotherapy: A Case Report.

Pancreatic hepatoid carcinoma (HC) is a heterogeneous tumor with high degree of malignancy and poor prognosis, which display cytological and/or structural features of focal hepatocellular carcinoma (HCC). For the low incidence and atypical clinical symptoms, it is possible to be diagnosed as pancreatic cancer before operation, and mainly depending on the pathological examination. To the best of our knowledge, surgery combined with radiotherapy and chemotherapy is the common treatment of pancreatic HC. However, the curative effect and prognosis is poor. We report a case of 44-year-old woman with pancreatic HC treated with PD-1 receptor inhibitor and transarterial chemoembolization, whose clinical symptoms and laboratory indexes are significantly improved after treatment.

MicroRNA-506-3p inhibits colorectal cancer cell proliferation through targeting enhancer of zeste homologue 2.

A large number of studies have shown that microRNA (miRNA) has an important relationship with the occurrence and development of colorectal cancer (CRC), but its specific molecular mechanism has not been fully elucidated. This study is to explore the influence of miR-506-3p on the malignant behavior of CRC and its underlying molecular mechanism. Our results show that miR-506-3p was lowly expressed and enhancer of zeste homologue 2 (EZH2) was highly expressed in CRC. Overexpressing miR-506-3p or silencing EZH2 inhibited CRC cell proliferation, migration and invasion and promoted apoptosis. Inhibiting miR-506-3p promoted CRC cell proliferation, migration and invasion but inhibited apoptosis. These impacts were reversed after co-transfecting si-EZH2. Further mechanism studies have shown that miR-506-3p can reduce EZH2 expression in CRC cells by binding to the 3'UTR end of EZH2. In summary, the results of this study show that miR-506-3p inhibited CRC progression through targeting EZH2 expression. This provides a new molecular target for the clinical treatment of CRC in the future.

Hypothermic oxygenated perfusion with defatting cocktail further improves steatotic liver grafts in a transplantation rat model.

In this study, we evaluated the restoring and defatting effect of hypothermic oxygenated perfusion (HOPE) on severe steatotic liver grafts with a defatting cocktail (DF) in a rat model. Severe (≥60%) hepatic macrosteatosis was induced by a high-fat diet (HFD) for 6 weeks, after which the rats were randomly divided into four following groups: Control group, with lean livers being preserved in static cold storage (SCS) at 0°C-4°C for 45 minutes; SCS group, with a steatotic liver graft (SLG) being preserved in SCS at 0°C-4°C for 4 hours; HOPE group, where SLG was perfused with 3-hours HOPE followed by 1-hours SCS; and HOPE + DF group, HOPE with the addition of DF. Graft function after orthotopic liver transplantation was assessed in terms of mitochondrial function (adenosine triphosphate [ATP], Glycogen), endoplasmic reticulum stress (PPY, GRP78, CHOP, and ATF-6), cell apoptosis (Tunel assay, Caspase-3), inflammatory level (HMGB1, TLR4, IL-1ß, IL-6. TNF-α, Factor V), and posttransplantation survival. HOPE protected steatotic liver grafts from microcirculation disturbance and endoplasmic reticulum stress and then promoted ATP and glycogen synthesis that improved mitochondrial function. Meanwhile, under conditions of ischemia-reperfusion injury, it prevented nuclear injury and endothelial damage by suppressing the release of an inflammatory mediator. The high efficacy of HOPE was enhanced after the addition of the DF. DF agents cannot promote the lipid decomposition of the steatotic liver graft at 0°C-4°C, but they can further improve steatotic liver and postoperative survival compared to the HOPE. The defatted steatotic liver grafts can be safely used in rat orthotopic liver transplantation.

Prenatal diagnosis and postnatal management of congenital mesoblastic nephroma: Experience at a single center in China.

OBJECTIVE: To review the prenatal and postnatal clinical characteristics and pathological subtypes, as well as the surgical outcome for congenital mesoblastic nephroma (CMN) cases. METHOD: A retrospective review was performed in 11 cases with CMN prenatally diagnosed at a single center between 2015 and 2019. The clinical characteristics, surgical outcome, histopathology, and follow-up were retrospectively obtained and reviewed. RESULTS: The median gestational age at which the sonographic diagnosis was made was 35 weeks. Polyhydramnios was found in four (36.4%) cases, and all resulted in a preterm birth. Nine infants had hypertension. Ten cases underwent radical nephrectomy, and one underwent radical nephrectomy and partial adrenalectomy. The pathological results showed that six tumors were classical variants, four mixed variants, and one was a cellular variant. Three cases presented as a stage I, eight as stage II, and no stage III or IV cases were diagnosed. All patients are alive so far. At a median follow-up of 14 months, no local recurrence, or remote metastases were found. CONCLUSION: The prognosis of prenatal CMN cases is excellent after early surgery.

Recent progress in cadmium fluorescent and colorimetric probes.

Cadmium is a heavy metal which exists widely in industrial and agricultural production and can induce a variety of diseases in organisms. Therefore, its detection is of great significance in the fields of biology, environment and medicine. Fluorescent probe has been a powerful tool for cadmium detection because of its convenience, sensitivity, and bioimaging capability. In this paper, we reviewed 98 literatures on cadmium fluorescent sensors reported from 2017 to 2021, classified them according to different fluorophores, elaborated the probe design, application characteristics and recognition mode, summarized and prospected the development of cadmium fluorescent and colorimetric probes. We hope to provide some help for researchers to design cadmium fluorescent probes with higher selectivity, sensitivity and practicability.

Comparison of transcatheter arterial chemoembolization with raltitrexed plus liposomal doxorubicin vs. tegafur plus pirarubicin for unresectable hepatocellular carcinoma.

BACKGROUND: There is still no general consensus on the optimal chemotherapeutic agent selection for transcatheter arterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC). The present study aimed to compare the efficacy and safety of TACE with raltitrexed plus liposomal doxorubicin (R + PGLD) vs. tegafur plus pirarubicin (T + P) in patients with unresectable HCC. METHODS: A total of 148 patients with unresectable HCC treated with TACE between January 2012 and December 2016 were retrospectively analyzed. Of them, 74 patients were in the R + PGLD group and 74 patients were in the T + P group (1:1). The treatment response of the tumor, overall survival (OS) time, and adverse effects were compared between the two groups. RESULTS: There were no significant differences in patient characteristics or embolization effect (lipiodol deposition) between the two groups (P>0.05). R + PGLD treatment had a better clinical efficacy than T + P treatment (OR: 64.9% vs. 45.9%, P=0.031; DC: 89.2% vs. 74.3%, P=0.032). Portal vein invasion, hepatic vein invasion, tumor size and BCLC stage were associated with OR or DC after TACE using R + PGLD treatment. Survival analysis revealed that patients who received TACE with R + PGLD had a better prognosis than those treated with T + P. Moreover, some complications in the R + PGLD group, including vomiting, myelosuppression and cardiotoxicity, were significantly lower than those in the T + P group (P<0.05). CONCLUSIONS: TACE with raltitrexed and liposomal doxorubicin could reduce the incidence of adverse reactions and significantly improve the OS of patients with unresectable HCC.

Intrahepatic T helper 17 cells recruited by hepatitis B virus X antigen-activated hepatic stellate cells exacerbate the progression of chronic hepatitis B virus infection.

Immunopathological injury induced by persistent hepatitis B virus (HBV) infection contributes to the progression from chronic hepatitis B (CHB) to hepatic cirrhosis and hepatocellular carcinoma (HCC). Regulatory T cells (Tregs), CD4+ T helper (Th) cells, and hepatic stellate cells (HSCs) are considered to be the pivotal factors during this progression. In this study, our aim was to investigate the molecular mechanisms of liver immunopathological injury associated with Tregs, CD4+ Th cells, and HSCs. Liver tissues were collected to assay the cytokines and distribution and frequencies of CD4+ Th cells and Tregs. The chemotaxis of Th17 cells towards the liver and the interactions between IL-22, IL-17A, and HSCs were explored. The data showed the frequencies of Th17 cells, and their effector molecules IL-22 and IL-17A were increased along with the severity of chronic liver diseases. However, the frequencies of Tregs were decreased in HBV-associated cirrhotic tissues compared with those in CHB tissues and HCC tissues. hepatitis B virus X antigen (HBxAg)-activated HSCs recruited more Th17 cells into the liver and conduced to the secretion of IL-17A and IL-22 that could in turn stimulate the proliferation and fibrotic marker secretion of the HSCs. Therefore, we suggest that the interactions between Th17 cells, IL-17A, IL-22, and HSCs form a positive feedback loop that aggravated the progression of chronic liver disease with HBV infection through the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) signalling pathway. Our findings indicated the IL-17A/IL-22 pathway might become a new treatment target for liver cirrhosis and HCC.

PIAS4, upregulated in hepatocellular carcinoma, promotes tumorigenicity and metastasis.

Protein inhibitor of activated STAT4 (PIAS4) protein has been implicated in regulating various biological activities including protein posttranslational modification, such as SUMOylation. In this study, we explored the roles of PIAS4 in hepatocellular carcinoma (HCC). We analyzed the PIAS4 expression in cancer tissues and paracancerous tissues from 38 HCC patients and its correlation with patients' prognosis. In vitro, PIAS4 was overexpressed or knockdowned in Huh-7 and HepG-2 cells. Then Cell Counting Kit-8 assay, flow cytometry, and Transwell assay were performed to assess cell viability, apoptosis, migration, and invasion, respectively. Furthermore, SUMOylation of AMPKα and NEMO mediated by PIAS4 was investigated. The results showed that the PIAS4 expression was significantly upregulated in cancer tissues and was correlated with poor prognosis in HCC patients. PIAS4 silencing blocked the SUMOylation of AMPKα and NEMO, leading to enhanced cell proliferation, migration, and invasion. In addition, inhibition of AMPKα or NEMO by siRNAs attenuated the effect of PIAS4 silencing on Huh-7 and HepG-2 cells. In summary, our findings suggest that PIAS4 promotes tumorigenicity and metastasis of HCC cells by promoting the SUMOylation of AMPKα and NEMO.

LETM1 Knockdown Promotes Autophagy and Apoptosis Through AMP-Activated Protein Kinase Phosphorylation-Mediated Beclin-1/Bcl-2 Complex Dissociation in Hepatocellular Carcinoma.

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is an inner mitochondrial membrane protein that has been reported to be involved in many primary tumors and may regulate many biological processes. However, the biological role and molecular mechanism of LETM1 in the progression of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we found that LETM1 was highly expressed in HCC tissues and cell lines and that higher LETM1 expression was associated with a lower overall survival rate in HCC patients. In addition, knockdown of LETM1 inhibited proliferation and enhanced apoptosis and autophagy in the Huh 7 and QGY-7701 liver cancer cell lines. Mechanistically, knockdown of LETM1 dissociated the Beclin-1/Bcl-2 complex through phosphorylation of AMPK and Bcl-2. These results demonstrated that LETM1 is involved in the development of HCC and could be a novel therapeutic target in HCC.