IRG1 restrains M2 macrophage polarization and suppresses intrahepatic cholangiocarcinoma progression via the CCL18/STAT3 pathway.

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant and aggressive cancer whose incidence and mortality continue to increase, whereas its prognosis remains dismal. Tumor-associated macrophages (TAMs) promote malignant progression and immune microenvironment remodeling through direct contact and secreted mediators. Targeting TAMs has emerged as a promising strategy for ICC treatment. Here, we revealed the potential regulatory function of immune responsive gene 1 (IRG1) in macrophage polarization. We found that IRG1 expression remained at a low level in M2 macrophages. IRG1 overexpression can restrain macrophages from polarizing to the M2 type, which results in inhibition of the proliferation, invasion, and migration of ICC, whereas IRG1 knockdown exerts the opposite effects. Mechanistically, IRG1 inhibited the tumor-promoting chemokine CCL18 and thus suppressed ICC progression by regulating STAT3 phosphorylation. The intervention of IRG1 expression in TAMs may serve as a potential therapeutic target for delaying ICC progression.

TMEM147 aggravates the progression of HCC by modulating cholesterol homeostasis, suppressing ferroptosis, and promoting the M2 polarization of tumor-associated macrophages.

BACKGROUND: The endoplasmic reticulum (ER) regulates critical processes, including lipid synthesis, which are affected by transmembrane proteins localized in the ER membrane. One such protein, transmembrane protein 147 (TMEM147), has recently been implicated for its role in hepatocellular carcinoma (HCC) tumorigenesis; however, the mechanisms remain unclear. We investigated the role of TMEM147 in HCC and the underlying mechanisms. METHODS: TMEM147 expression was examined in human HCC cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of TMEM147 on the progression of HCC. Proteins interacting with TMEM147 were identified via RNA-seq, immunoprecipitation, and mass spectrometry analyses. Lipidomic analysis and enzyme-linked immunosorbent assay (ELISA) were employed to determine and analyze cholesterol and 27-hydroxycholesterol (27HC) contents. Extensive experimental techniques were used to study ferroptosis in HCC cells. The fatty acid content of macrophages affected by TMEM147 was quantified using ELISA. Macrophage phenotypes were determined using immunofluorescence assay and flow cytometric analysis. RESULTS: TMEM147 mRNA and protein levels were increased in HCC cells, and the increased TMEM147 expression was associated with a poor survival. TMEM147 promoted tumor cell proliferation and metastases in vitro and in vivo. The protein was found to interact with the key enzyme 7-dehydrocholesterol reductase (DHCR7), which affected cellular cholesterol homeostasis and increased the extracellular levels of 27HC in HCC cells. TMEM147 also promoted the expression of DHCR7 by enhancing the activity of signal transducer and activator of transcription 2. 27HC expression upregulated glutathione peroxidase 4 in HCC, leading to ferroptosis resistance and promotion of HCC proliferation. HCC cell-derived 27HC expression increased the lipid metabolism in macrophages and activated peroxisome proliferator-activated receptor-γ signaling, thereby activating M2 macrophage polarization and promoting HCC cell invasion and migration. CONCLUSIONS: Our results indicate that TMEM147 confers ferroptosis resistance and M2 macrophage polarization, which are primarily dependent on the upregulation of cellular cholesterol homeostasis and 27HC secretion, leading to cancer growth and metastasis. These findings suggest that the TMEM147/STAT2/DHCR7/27HC axis in the tumor microenvironment may serve as a promising therapeutic target for HCC.

HLTF promotes hepatocellular carcinoma progression by enhancing SRSF1 stability and activating ERK/MAPK pathway.

Helicase-like transcription factor (HLTF) has been found to be involved in the progression of several tumors, but the role of HLTF in hepatocellular carcinoma (HCC) progression has not been studied. Here, our study explored the underlying mechanism of HLTF in HCC progression for the first time. Database analysis and clinical sample examination indicated that HLTF was upregulated in HCC tissues and was related to poor clinicopathological features in patients. Upregulation of HLTF accelerated the growth and metastasis of HCC cells both in vitro and in vivo. Bioinformatics analysis and subsequent experiments revealed that ERK/MAPK signaling pathway activation was vital to HLTF-mediated proliferation and metastasis in HCC cells. Moreover, HLTF was demonstrated to interact with SRSF1 and contribute to its protein stability to activate the ERK/MAPK signaling pathway and enhance HCC growth and metastasis. In addition, miR-511-5p was expressed at a low level in HCC tissues, was negatively correlated HLTF, and regulated HLTF expression. Our study shows that HLTF plays an oncogenic role in HCC progression and provides a novel biomarker and therapeutic target for the diagnosis and treatment of HCC.

LncRNA Hnf4αos exacerbates liver ischemia/reperfusion injury in mice via Hnf4αos/Hnf4α duplex-mediated PGC1α suppression.

LncRNAs are involved in the pathophysiologic processes of multiple diseases, but little is known about their functions in hepatic ischemia/reperfusion injury (HIRI). As a novel lncRNA, the pathogenetic significance of hepatic nuclear factor 4 alpha, opposite strand (Hnf4αos) in hepatic I/R injury remains unclear. Here, differentially expressed Hnf4αos and Hnf4α antisense RNA 1 (Hnf4α-as1) were identified in liver tissues from mouse ischemia/reperfusion models and patients who underwent liver resection surgery. Hnf4αos deficiency in Hnf4αos-KO mice led to improved liver function, alleviated the inflammatory response and reduced cell death. Mechanistically, we found a regulatory role of Hnf4αos-KO in ROS metabolism through PGC1α upregulation. Hnf4αos also promoted the stability of Hnf4α mRNA through an RNA/RNA duplex, leading to the transcriptional activation of miR-23a and miR-23a depletion was required for PGC1α function in hepatoprotective effects on HIRI. Together, our findings reveal that Hnf4αos elevation in HIRI leads to severe liver damage via Hnf4αos/Hnf4α/miR-23a axis-mediated PGC1α inhibition.

NNMT promotes the progression of intrahepatic cholangiocarcinoma by regulating aerobic glycolysis via the EGFR-STAT3 axis.

Nicotinamide N-methyltransferase (NNMT), a member of the N-methyltransferase family, plays an important role in tumorigenesis. However, its expression and biological functions in intrahepatic cholangiocarcinoma (iCCA) remain to be established. In our study, we identified NNMT as an oncogene in iCCA and provided mechanistic insights into the roles of NNMT in iCCA progression. High NNMT expression in iCCA tissues was identified using western blotting and immunohistochemistry (IHC). We identified a significantly higher NNMT expression level in human iCCA tissues than that in adjacent normal tissues. Increased NNMT expression promoted iCCA cell proliferation and metastasis in vitro and in vivo. Mechanistically, NNMT inhibited the level of histone methylation in iCCA cells by consuming the methyl donor S-adenosyl methionine (SAM), thereby promoting the expression of epidermal growth factor receptor (EGFR). EGFR may activate the aerobic glycolysis pathway in iCCA cells by activating the STAT3 signaling pathway. In conclusion, we identified NNMT as an oncogene in iCCA and provided mechanistic insights into the roles of NNMT in iCCA progression.

Integrative Analysis of the Roles of lncRNAs and mRNAs in Itaconate-Mediated Protection Against Liver Ischemia-Reperfusion Injury in Mice.

PURPOSE: Itaconate is well known for its strong anti-inflammatory and antioxidant effect, but little is known about the potential role of long non-coding RNAs (lncRNAs) in the underlying mechanisms of hepatic ischemia-reperfusion (IR) injury. The aim of our study is to identify lncRNAs related to IR injury and itaconate-mediated protection and to demonstrate the mechanism by which itaconate acts in liver IR injury from the new perspective of lncRNAs. METHODS: 4-Octyl itaconate (OI), a membrane-permeable derivative of itaconate, was used as a substitute for itaconate in our study. By using a mouse model of hepatic IR injury, serum and liver samples were collected to measure indexes of liver injury. Then, the liver samples of the mice were subjected to RNA sequencing (RNA-seq) and subsequent bioinformatics analysis. RESULTS: Itaconate attenuated liver IR injury. A total of 138 lncRNAs and 156 messenger RNAs (mRNAs) were markedly differentially expressed in the IR-damaged liver tissues pretreated with OI compared with the matched liver tissues treated with vehicle. Functional analysis indicated that lncRNAs may indirectly participate in the effects of itaconate. Furthermore, 41 mRNAs were examined for the protein-protein interaction (PPI) network analysis, and a key gene cluster was defined. Then, combined the coexpression analysis and the cis and trans regulatory function prediction of lncRNAs, some "candidate" lncRNA-mRNA pairs which might relate to itaconate-mediated liver protection were identified, while the relationship requires future validation. CONCLUSION: Our study revealed that itaconate could protect the liver against IR injury and that lncRNAs might play a role in this process. Our study provides a novel way to investigate the mechanism by which itaconate affects hepatic IR injury and exerts its anti-inflammatory and antioxidative stress effects.

PGC-1α Protects against Hepatic Ischemia Reperfusion Injury by Activating PPARα and PPARγ and Regulating ROS Production.

Peroxisome proliferator-activated receptors (PPARs) α and γ have been shown to be protective in hepatic ischemia/reperfusion (I/R) injury. However, the precise role of PPARγ coactivator-1α (PGC-1α), which can coactivate both of these receptors, in hepatic I/R injury, remains largely unknown. This study was designed to test our hypothesis that PGC-1α is protective during hepatic I/R injury in vitro and in vivo. Our results show that endogenous PGC-1α is basally expressed in normal livers and is moderately increased by I/R. Ectopic PGC-1α protects against hepatic I/R and hepatocyte anoxia/reoxygenation (A/R) injuries, whereas knockdown of endogenous PGC-1α aggravates such injuries, as evidenced by assessment of the levels of serum aminotransferases and inflammatory cytokines, necrosis, apoptosis, cell viability, and histological examination. The EMSA assay shows that the activation of PPARα and PPARγ is increased or decreased by the overexpression or knockdown of PGC-1α, respectively, during hepatic I/R and hepatocyte A/R injuries. In addition, the administration of specific antagonists of either PPARα (MK886) or PPARγ (GW9662) can effectively decrease the protective effect of PGC-1α against hepatic I/R and hepatocyte A/R injuries. We also demonstrate an important regulatory role of PGC-1α in reactive oxygen species (ROS) metabolism during hepatic I/R, which is correlated with the induction of ROS-detoxifying enzymes and is also dependent on the activations of PPARα and PPARγ. These data demonstrate that PGC-1α protects against hepatic I/R injury, mainly by regulating the activation of PPARα and PPARγ. Thus, PGC-1α may be a promising therapeutic target for the protection of the liver against I/R injury.

Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target.

Cholangiocarcinoma (CCA) is an aggressive and multifactorial malignancy of the biliary tract. The carcinogenesis of CCA is associated with genomic and epigenetic abnormalities, as well as environmental effects. However, early clinical diagnosis and reliable treatment strategies of CCA remain unsatisfactory. Multiple compartments of the tumor microenvironment significantly affect the progression of CCA. Tumor-associated macrophages (TAMs) are a type of plastic immune cells that are recruited and activated in the CCA microenvironment, especially at the tumor invasive front and perivascular sites. TAMs create a favorable environment that benefits CCA growth by closely interacting with CCA cells and other stromal cells via releasing multiple protumor factors. In addition, TAMs exert immunosuppressive and antichemotherapeutic effects, thus intensifying the malignancy. Targeting TAMs may provide an improved understanding of, and novel therapeutic approaches for, CCA. This review focuses on revealing the interplay between TAMs and CCA.

Unfolded protein response in colorectal cancer.

Colorectal cancer (CRC) is a gastrointestinal malignancy originating from either the colon or the rectum. A growing number of researches prove that the unfolded protein response (UPR) is closely related to the occurrence and progression of colorectal cancer. The UPR has three canonical endoplasmic reticulum (ER) transmembrane protein sensors: inositol requiring kinase 1 (IRE1), pancreatic ER eIF2α kinase (PERK), and activating transcription factor 6 (ATF6). Each of the three pathways is closely associated with CRC development. The three pathways are relatively independent as well as interrelated. Under ER stress, the activated UPR boosts the protein folding capacity to maximize cell adaptation and survival, whereas sustained or excessive ER triggers cell apoptosis conversely. The UPR involves different stages of CRC pathogenesis, promotes or hinders the progression of CRC, and will pave the way for novel therapeutic and diagnostic approaches. Meanwhile, the correlation between different signal branches in UPR and the switch between the adaptation and apoptosis pathways still need to be further investigated in the future.

The PGC1α/NRF1-MPC1 axis suppresses tumor progression and enhances the sensitivity to sorafenib/doxorubicin treatment in hepatocellular carcinoma.

Targeting energy metabolism holds the potential to effectively treat a variety of malignant diseases, and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a key regulator of energy metabolism. However, PGC1α's role in cancer, especially in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we reported that PGC1α was significantly downregulated in HCC cell lines and specimens. Moreover, reduced expression of PGC1α in tumor cells was correlated with poor prognosis. PGC1α overexpression substantially inhibited cell proliferation and induced apoptosis in vitro and in vivo. On the contrary, the knockdown of PGC1α produced the opposite effect. The mechanism was at least partially due to the upregulation of mitochondrial pyruvate carrier 1 (MPC1) caused by PGC1α, which promoted mitochondrial biogenesis by binding to nuclear respiratory factor 1 (NRF1). Consequently, the production of cellular reactive oxygen species (ROS) caused by mitochondrial oxidation was elevated above a critical threshold for survival. Furthermore, we found that PGC1α could enhance the antitumor activity of sorafenib and doxorubicin in HCC through ROS accumulation-mediated cell death. These results indicate that PGC1α/NRF1-MPC1 axis is involved in HCC progression and could be a promising target for HCC treatment.

Clinical characteristics and management of 1572 patients with pyogenic liver abscess: A 12-year retrospective study.

BACKGROUND & AIMS: Pyogenic liver abscesses (PLA) are space-occupying lesions in the liver that produce high morbidity and mortality. The clinical characteristics and prognosis of abscesses is different depending on the bacterial culture results and require different strategies for management. The aim of this study was to investigate the clinical characteristics and prognostic factors of patients with PLA. METHODS: Clinical features, laboratory tests and etiology of PLA between 2006 to 2011 and 2012 to 2017 in a single hospital were retrospectively reviewed. The incidence and mortality of PLA caused by Escherichia coli and Klebsiella pneumoniae were compared and the risk factors for multiple organ dysfunction (MODS) and endophthalmitis were evaluated. RESULTS: Among the 1,572 PLA patients, the proportion with PLA increased from 333 (21.2%) in 2006-2011 to 1,239 (78.8%) in 2012-2017 without any investigation and treatment procedure differences. K pneumoniae was the main isolate in analysed pus cultures (85.6%). The mortality rate of patients with K pneumoniae infection was lower in the latter period (6.7% vs 0.7%, P = .035). Multivariate analyses revealed that age, fever, MODS and length of hospital stay were factors affecting poor prognosis (death + unhealed/uncured) in PLA patients after treatment and that cardiovascular disease, pleural effusion and pulmonary infection were risk factors for MODS, while diabetes mellitus was the only risk factor for endophthalmitis. Most patients (95.5%) with PLA recovered after abscess drainage/puncture and antibiotic therapy. CONCLUSIONS: Pleural effusion, fever, MODS and length of hospital stays were factors useful in predicting PLA outcomes.

Consensus recommendations of three-dimensional visualization for diagnosis and management of liver diseases.

Three-dimensional (3D) visualization involves feature extraction and 3D reconstruction of CT images using a computer processing technology. It is a tool for displaying, describing, and interpreting 3D anatomy and morphological features of organs, thus providing intuitive, stereoscopic, and accurate methods for clinical decision-making. It has played an increasingly significant role in the diagnosis and management of liver diseases. Over the last decade, it has been proven safe and effective to use 3D simulation software for pre-hepatectomy assessment, virtual hepatectomy, and measurement of liver volumes in blood flow areas of the portal vein; meanwhile, the use of 3D models in combination with hydrodynamic analysis has become a novel non-invasive method for diagnosis and detection of portal hypertension. We herein describe the progress of research on 3D visualization, its workflow, current situation, challenges, opportunities, and its capacity to improve clinical decision-making, emphasizing its utility for patients with liver diseases. Current advances in modern imaging technologies have promised a further increase in diagnostic efficacy of liver diseases. For example, complex internal anatomy of the liver and detailed morphological features of liver lesions can be reflected from CT-based 3D models. A meta-analysis reported that the application of 3D visualization technology in the diagnosis and management of primary hepatocellular carcinoma has significant or extremely significant differences over the control group in terms of intraoperative blood loss, postoperative complications, recovery of postoperative liver function, operation time, hospitalization time, and tumor recurrence on short-term follow-up. However, the acquisition of high-quality CT images and the use of these images for 3D visualization processing lack a unified standard, quality control system, and homogeneity, which might hinder the evaluation of application efficacy in different clinical centers, causing enormous inconvenience to clinical practice and scientific research. Therefore, rigorous operating guidelines and quality control systems need to be established for 3D visualization of liver to develop it to become a mature technology. Herein, we provide recommendations for the research on diagnosis and management of 3D visualization in liver diseases to meet this urgent need in this research field.

The circular RNA circMAST1 promotes hepatocellular carcinoma cell proliferation and migration by sponging miR-1299 and regulating CTNND1 expression.

Circular RNAs (circRNAs) are a class of non-coding RNAs with a loop structure; however, their functions remain largely unknown. Growing evidence suggests that circRNAs play a pivotal role in the progression of malignant diseases. However, the expression profiles and function of circRNAs in hepatocellular carcinoma (HCC) remain unclear. We investigated the expression of microtubule-associated serine/threonine kinase 1 (MAST1) circRNA (circMAST1) in HCC and healthy tissues using bioinformatics, quantitative real-time PCR (qRT-PCR), and fluorescence in situ hybridization. Luciferase reporter assays were performed to assess the interaction between circMAST1 and miR-1299. Proliferation assays, colony formation assays, flow cytometry, transwell assays, and western blotting were also performed. A mouse xenograft model was also used to determine the effect of circMAST1 on HCC growth in vivo. CircMAST1 was upregulated in HCC tissues and cell lines; silencing via small interfering RNA inhibited migration, invasion, and proliferation of HCC cell lines in vitro as well as tumor growth in vivo. Furthermore, the expression of circMAST1 was positively correlated with catenin delta-1 (CTNND1) and negatively correlated with microRNA (miR)-1299 in HCC clinical samples. Importantly, circMAST1 sponged miR-1299 to stabilize the expression of CTNND1 and promoted tumorigenic features in HCC cell lines. We found that circMAST1 may serve as a novel biomarker for HCC. Moreover, circMAST1 elicits HCC progression by sponging miRNA-1299 and stabilizing CTNND1. Our data provide potential options for therapeutic targets in patients with HCC.

The immunoglobulin superfamily member 3 (IGSF3) promotes hepatocellular carcinoma progression through activation of the NF-κB pathway.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) suffer from a high fatality rate, likely due to increased incidence of tumor relapse and metastasis. Understanding the molecular mechanisms that contribute to HCC development and progression is vital for the discovery of new treatment targets. This study aims to explore the expression profiles and functions of immunoglobulin superfamily member 3 (IGSF3) in HCC. METHODS: We evaluated IGSF3 levels in HCC and normal tissues using bioinformatics, western blot, quantitative real-time PCR (qRT-PCR), and immunohistochemistry. We also conducted proliferation assays, colony formation assays, flow cytometry, cell migration assay, cell invasion assay, qRT-PCR, and western blotting in HCC cell lines. Immunofluorescence and western blotting further used to study the IGSF3 pathway. A mouse xenograft model was utilized to examine the influence of IGSF3 on HCC growth in vivo. RESULTS: IGSF3 levels were higher in HCC tissues and cell lines. Silencing of IGSF3 via lentiviral vector system (LV) inhibited migration, invasion, and growth of HCC cell lines in vitro as well as tumor growth in vivo. Overexpression of IGSF3 promoted result in vitro. Importantly, we found that IGSF3 activates the NF-κB pathway to promote tumorigenic features in HCC cell lines. CONCLUSIONS: We found that IGSF3 can be used as a novel biomarker for HCC detection. Moreover, IGSF3 elicits HCC progression by activating the NF-κB pathway. As such, our data provides potential options for therapeutic targets in patients with HCC.

lncRNA-SOX2OT promotes hepatocellular carcinoma invasion and metastasis through miR-122-5p-mediated activation of PKM2.

Tumor cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect, but the involvement of Warburg effect in liver cancer cell metastasis is not well understood. In present study, our results indicate a positive correlation between glucose metabolism level and metastatic potential of hepatocellular carcinoma (HCC). We also observed that a long noncoding RNA-SOX2OT (lncRNA-SOX2OT) can not only increase the metastatic potential of HCC but also promote a pyruvate kinase M2 (PKM2)-mediated activation of glucose metabolism. Inhibition of PKM2 in HCC cells greatly compromises lncRNA-SOX2OT in promoting Warburg effect and metastasis. Furthermore, miR-122-5p was found being a direct target of lncRNA-SOX2OT in regulating PKM2 expression. Thus, our findings reveal that lncRNA-SOX2OT, a regulator of PKM2, could predispose HCC patients to metastases and may serve as a candidate for metastatic prediction and therapies in HCC patients.

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and its mortality continues to rise globally. Because of its high heterogeneity and complex molecular landscapes, published gene signatures have demonstrated low specificity and robustness. Functional signatures containing a group of genes involved in similar biological functions may display a more robust performance. METHODS: The present study was designed to excavate potential functional signatures for PDAC by analyzing maximal number of datasets extracted from available databases with a recently developed method of FAIME (Functional Analysis of Individual Microarray Expression) in a comprehensive and integrated way. RESULTS: Eleven PDAC datasets were extracted from GEO, ICGC and TCGA databases. By systemically analyzing these datasets, we identified a robust functional signature of subpathway (path:00982_1), which belongs to the drug metabolism-cytochrome P450 pathway. The signature has displayed a more powerful and robust capacity in predicting prognosis, drug response and chemotherapeutic efficacy for PDAC, particularly for the classical subtype, in comparison with published gene signatures and clinically used TNM staging system. This signature was verified by meta-analyses and validated in available cell line and clinical datasets with chemotherapeutic efficacy. CONCLUSION: The present study has identified a novel functional PDAC signature, which has the potential to improve the current systems for predicting the prognosis and monitoring drug response, and to serve a linkage to therapeutic options for combating PDAC. However, the involvement of path:00982_1 subpathway in the metabolism of anti-PDAC chemotherapeutic drugs, particularly its biological interpretation, requires a further investigation. Video Abstract.

BIRC7 promotes epithelial-mesenchymal transition and metastasis in papillary thyroid carcinoma through restraining autophagy.

Papillary thyroid carcinoma (PTC) is the most common cancer of the endocrine system, which is usually associated with a favorable therapeutic response and prognosis. However, metastatic spreading occurs in around 5% of the PTC patients. Identification of molecular markers could early predict the metastatic potential, which is essential for reducing the patient's overtreatment. Baculoviral IAP Repeat Containing 7 (BIRC7) is an inhibitor of apoptosis protein (IAP) family gene that is known to be linked to tumor progression, but its role in the setting of PTC metastasis remains unknown. This study, therefore, aims to explore the role of BIRC7 in the metastasis and autophagy of PTC and elucidate its underlying molecular mechanisms. BIRC7 expression was assessed in fresh samples of human PTC and normal tissues via qRT-PCR and immunohistochemistry. In addition, BIRC7 was overexpressed and silenced in PTC cell lines followed by transmission electron microscopy, western blotting, immunofluorescence microscopy, wound healing and invasion assays. We further explored the relevance of BIRC7 in vivo using a tumor xenograft model. Our results demonstrated that BIRC7 plays a pro-invasive role in PTC. BIRC7 expression is significantly upregulated in PTC compared with matched thyroid normal tissues. In addition, we found that BIRC7 knockdown induced a significant reduction in PTC cell EMT and metastasis in vitro and in vivo, while overexpression of BIRC7 markedly enhanced PTC cell migration and invasion. Moreover, our data showed that BIRC7 was able to suppress autophagy through modulating the expression of ATG5 and BECN1, and that this suppression is responsible for BIRC7 silence induced suppression of EMT and metastasis of PTC cell. We further found that targeting both BIRC7 and mTOR enhances autophagy in PTC cells and to achieve synergistic antimetastatic efficacy in vitro and in vivo. These findings indicate that the suppression of autophagy by BIRC7 drives the invasion and metastasis of PTC cells, thus suggesting that the activation of autophagy may inhibit metastasis of PTC with high BIRC7 expression.

Identification of Hub Genes Associated With Development and Microenvironment of Hepatocellular Carcinoma by Weighted Gene Co-expression Network Analysis and Differential Gene Expression Analysis.

A further understanding of the molecular mechanism of hepatocellular carcinoma (HCC) is necessary to predict a patient's prognosis and develop new targeted gene drugs. This study aims to identify essential genes related to HCC. We used the Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene expression analysis to analyze the gene expression profile of GSE45114 in the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas database (TCGA). A total of 37 overlapping genes were extracted from four groups of results. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were performed on the 37 overlapping genes. Then, we used the STRING database to map the protein interaction (PPI) network of 37 overlapping genes. Ten hub genes were screened according to the Maximal Clique Centrality (MCC) score using the Cytohubba plugin of Cytoscape (including FOS, EGR1, EPHA2, DUSP1, IGFBP3, SOCS2, ID1, DUSP6, MT1G, and MT1H). Most hub genes show a significant association with immune infiltration types and tumor stemness of microenvironment in HCC. According to Univariate Cox regression analysis and Kaplan-Meier survival estimation, SOCS2 was positively correlated with overall survival (OS), and IGFBP3 was negatively correlated with OS. Moreover, the expression of IGFBP3 increased with the increase of the clinical stage, while the expression of SOCS2 decreased with the increase of the clinical stage. In conclusion, our findings suggest that SOCS2 and IGFBP3 may play an essential role in the development of HCC and may serve as a potential biomarker for future diagnosis and treatment.