Search

Hepatocellular carcinoma (HCC) was one of the most prevalent life-threatening cancers. Metastasis is the leading cause of cancer-related death in HCC. MiRNAs play essential roles in cancer metastasis.Expression of miR-652-3p in HCC was assessed. Function experiments of miR-652-3p and trinucleotide repeat-containing gene 6A protein (TNRC6A) were performed both in vitro and in vivo. mRNA sequencing, PCR, and western blot were performed to verify the target genes and pathway of miR-652-3p. The lung metastasis and xenograft cancer model in nude mice was established to investigate the effects of the miR-652-3p and TRNC6A on tumor metastasis in vivo. The relationship between the expression of the miR-652-3p, TNRC6A and the prognosis of HCC patients was analyzed.Upregulated miR-652-3p was found in the tumor tissues of HCC, especially in metastatic HCC patients. Overexpression of miR-652-3p promoted and knockdown of miR-652-3p suppressed HCC metastasis both in vitro and in vivo. MiR-652-3p promoted HCC metastasis via regulating the EMT pathway. TNRC6A was identified as a direct target of miR-652-3p, and the knockdown of TNRC6A restored repressed EMT and HCC metastasis caused by the inhibition of miR-652-3p. Clinical results revealed that high expression of miR-652-3p and low expression of TNRC6A were positively correlated to shortened overall survival and disease-free survival in HCC patients.MiR-652-3p promotes EMT and HCC metastasis by inhibiting TNRC6A expression in HCC. MiR-652-3p and TNRC6A may serve as potential biomarkers to predict prognosis in HCC patients with metastasis.

To screen transcription factor genes related to the prognosis of adult patients with sepsis.Twenty-three patients with sepsis and ten healthy individuals admitted for RNA-seq. Differential factors were enriched by four transcription factor databases, and survival analysis was adopted for core factors. Then, target genes were submitted to STRING to constitute the PPI network. Single-cell technology was used to localize cell lines. Finally, a transcription-target gene regulation network was constituted.A total of 4,224 DEGs were obtained between sepsis and NC groups. PPI results showed that FOXO3, NFKB1, SPI1, STAT5A, and PPARA were located in the center of the network. Target genes were related to cytokine-mediated signaling pathway and transcription regulator activity, etc. SPI1 was mainly located in monocyte cell lines, while FOXO3, PPARA, SP1, STAT3, and USF1 were expressed in monocyte cell lines, NK-T cell lines, and B cell lines. Compared with those in the control group, FOXO3, SP1, SPI1, STAT3, and USF1 were highly expressed in the sepsis group, while PPARA had low expression.Transcription factors such as FOXO3, PPARA, SP1, SPI1, STAT3, and USF1 are correlated with the prognosis of sepsis patients and thus may have a potential research value.Clinical Trial Registration: The clinical trial registration number is ChiCTR1900021261.

Targeting cytokinesis can suppress tumor growth by blocking cell division and promoting apoptosis. We aimed to characterize key cytokinesis regulator in hepatocellular carcinoma (HCC) progression, providing insights into identifying promising HCC therapeutic targets. The unbiased bioinformatic screening identified Anillin actin binding protein (ANLN) as a critical cytokinesis regulator involved in HCC development. Functional assay demonstrated that knockdown of ANLN inhibited HCC growth by inducing cytokinesis failure and DNA damage, leading to multinucleation and mitotic catastrophe. Mechanistically, ANLN acts as a scaffold to strengthen interaction between RACGAP1 and PLK1. ANLN promotes PLK1-mediated RACGAP1 phosphorylation and RhoA activation to ensure cytokinesis fidelity. To explore the function of ANLN in HCC tumorigenesis, we hydrodynamically transfected c-Myc and NRAS plasmids into Anln

Supplementary Data from Asialoglycoprotein Receptor 1 Functions as a Tumor Suppressor in Liver Cancer via Inhibition of STAT3

Liver cancer is characterized by aggressive growth and high mortality. Asialoglycoprotein receptor 1 (ASGR1), which is expressed almost exclusively in liver cells, is reduced in liver cancer. However, the specific mechanism of ASGR1 function in liver cancer has not been fully elucidated. On the basis of database screening, we identified ASGR1 as a tumor suppressor regulated by DNA methylation. Expression of ASGR1 was downregulated in liver cancer and correlated with tumor size, grade, and survival. Functional gain and loss experiments showed that ASGR1 suppresses the progression of liver cancer in vivo and in vitro. RNA sequencing and mass spectrometry showed that ASGR1 inhibits tyrosine phosphorylation of STAT3 by interacting with Nemo-like kinase (NLK). NLK bound the SH2 domain of STAT3 in an ATP-dependent manner and competed with glycoprotein 130 (GP130), ultimately suppressing GP130/JAK1-mediated phosphorylation of STAT3. ASGR1 altered the binding strength of NLK and STAT3 by interacting with GP130. Furthermore, the domain region of NLK was crucial for binding STAT3 and curbing its phosphorylation. Collectively, these results confirm that ASGR1 suppresses the progression of liver cancer by promoting the binding of NLK to STAT3 and inhibiting STAT3 phosphorylation, suggesting that approaches to activate the ASGR1–NLK axis may be a potential therapeutic strategy in this disease.Significance:ASGR1 downregulation by DNA methylation facilitates liver tumorigenesis by increasing STAT3 phosphorylation.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and its specific mechanism has not been fully elucidated. Inactivation of tumor suppressors may contribute to the occurrence, progression, and recurrence of HCC. DNA methylation is a crucial mechanism involved in regulating the occurrence of HCC. Herein, we aimed to identify the key methylation-related tumor suppressors as well as potential biomarkers and therapeutic targets in HCC. Methods: Combined analysis of TCGA and GEO databases was performed to obtain potential methylation-related tumor suppressors in HCC. Methyl-target sequencing was performed to analyze the methylation level of the GNA14 promoter. The diagnostic value of GNA14 as a predictor of HCC was evaluated in HCC tumor samples and compared with normal tissues. The functional role of GNA14 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro. Subcutaneous tumorigenesis, lung colonization, and orthotopic liver tumor model were performed to analyze the role of GNA14 in vivo. Results: The expression of GNA14 was found to be downregulated in HCC and it was negatively correlated with hepatitis B virus (HBV) infection, vascular invasion, and prognosis of HCC. DNA methylation was demonstrated to be responsible for the altered expression of GNA14 and was regulated by HBV-encoded X protein (HBx). GNA14 regulated the RB pathway by promoting Notch1 cleavage to inhibit tumor proliferation, and might inhibit tumor metastasis by inhibiting the expression of JMJD6. Conclusion: GNA14 could be regulated by HBx by modulating the methylation status of its promoter. We identified GNA14 as a potential biomarker and therapeutic target for HCC.

The farnesoid X receptor (FXR), as a bile acid (BA) sensor, plays an important role in the regulation of lipid metabolism. However, the effects and underlying molecular mechanisms of FXR on intestinal glucose homeostasis remain elusive. Herein, we demonstrated that FXR and glucose transporter 2 (GLUT2) are essential for BA‐mediated glucose homeostasis in the intestine. BA‐activated FXR enhanced glucose uptake in intestinal epithelial cells by increasing the expression of GLUT2, which depended on ERK1/2 phosphorylation via S1PR2. However, it also reduced the cell energy generation via inhibition of oxidative phosphorylation, which is crucial for intestinal glucose transport. Moreover, BA‐activated FXR signalling potently inhibited specific glucose flux through the intestinal epithelium to the circulation, which reduced the increase in blood glucose levels in mice following oral glucose administration. This trend was supported by the changed ratio of GLUT2 to SGLT1 in the brush border membrane (BBM), including especially decreased GLUT2 abundance in the BBM. Furthermore, impaired intestinal FXR signalling was observed in the patients with intestinal bile acid deficiency (IBAD). These findings uncover a novel function by which FXR sustains the intestinal glucose homeostasis and provide a rationale for FXR agonists in the treatment of IBAD‐related hyperglycaemia.

Significant enhancement of the glycolysis pathway is a major feature of tumor cells, even in the presence of abundant oxygen; this enhancement is known as the Warburg effect, and also called aerobic glycolysis. The Warburg effect was discovered nearly a hundred years ago, but its specific mechanism remains difficult to explain. DNA methylation is considered to be a potential trigger for the Warburg effect, as the two processes have many overlapping links during tumorigenesis. Based on a widely recognized potential mechanism of the Warburg effect, we here summarized the relationship between DNA methylation and the Warburg effect with regard to cellular energy metabolism factors, such as glycolysis related enzymes, mitochondrial function, glycolysis bypass pathways, the tumor oxygen sensing pathway and abnormal methylation conditions. We believe that clarifying the relationship between these different mechanisms may further help us understand how DNA methylation works on tumorigenesis and provide new opportunities for cancer therapy.

Background Metastasis serves as the leading cause of treatment failure and cancer-related death in HCC. The role of metastasis-associated miRNAs in HCC was elusive. Methods Combined analysis of TCGA data and exosomal miRNA sequencing data was performed. Expression of miR-652-3p in HCC was assessed. Function experiments of miR-652-3p and TNRC6A were performed both in vitro and in vivo. MRNA sequencing, PCR and western blot were performed to verify target genes and pathway of miR-652-3p. The lung metastasis and xenograft cancer model in nude mice was established to investigate the effects of miR-652-3p/TRNC6A axis on tumor metastasis in vivo. The potential transcription regulator of miR-652-3p was verified. The relationship of the expression of miR-652-3p/TNRC6A axis and prognosis of HCC patients was analyzed. Results Upregulated miR-652-3p was found in the tumor tissues of HCC, especially in metastatic HCC patients. Overexpression of miR-652-3p promoted and knockdown of miR-652-3p suppressed HCC metastasis both in vitro and in vivo. What’s more, miR-652-3p promoted HCC metastasis via regulating EMT pathway. Trinucleotide repeat-containing gene 6A protein (TNRC6A) was identified as a direct target of miR-652-3p, whose expression is negatively related with AFP level in HCC, and knockdown of TNRC6A promoted HCC metastasis. And knockdown of TNRC6A restored repressed EMT and HCC metastasis caused by inhibition of miR-652-3p. E2F1 transcriptionally promoted the expression of miR-652-3p through binding in the specific site in its DNA sequence. Besides, clinical results revealed that high expression of miR-652-3p and low expression of TNRC6A was positively correlated to shortened overall survival and disease-free survival in HCC patients. Conclusions The present study showed that E2F1 increases the expression of miR-652-3p, and miR-652-3p promotes EMT and HCC metastasis by directly inhibiting the expression of TNRC6A in HCC.

Liver cancer is characterized by aggressive growth and high mortality. Asialoglycoprotein receptor 1 (ASGR1), which is expressed almost exclusively in liver cells, is reduced in liver cancer. However, the specific mechanism of ASGR1 function in liver cancer has not been fully elucidated. On the basis of database screening, we identified ASGR1 as a tumor suppressor regulated by DNA methylation. Expression of ASGR1 was downregulated in liver cancer and correlated with tumor size, grade, and survival. Functional gain and loss experiments showed that ASGR1 suppresses the progression of liver cancer in vivo and in vitro. RNA sequencing and mass spectrometry showed that ASGR1 inhibits tyrosine phosphorylation of STAT3 by interacting with Nemo-like kinase (NLK). NLK bound the SH2 domain of STAT3 in an ATP-dependent manner and competed with glycoprotein 130 (GP130), ultimately suppressing GP130/JAK1-mediated phosphorylation of STAT3. ASGR1 altered the binding strength of NLK and STAT3 by interacting with GP130. Furthermore, the domain region of NLK was crucial for binding STAT3 and curbing its phosphorylation. Collectively, these results confirm that ASGR1 suppresses the progression of liver cancer by promoting the binding of NLK to STAT3 and inhibiting STAT3 phosphorylation, suggesting that approaches to activate the ASGR1–NLK axis may be a potential therapeutic strategy in this disease. Significance: ASGR1 downregulation by DNA methylation facilitates liver tumorigenesis by increasing STAT3 phosphorylation.

The in-phase/quadrature (I/Q) branches imbalance leads to mirror subcarrier interference and worsens the performance of zero-intermediate frequency (zero-IF)-based orthogonal frequency division multiplexing (OFDM) systems. To tackle the signal detection issue of in-phase/quadrature imbalance (IQI) at the transceiver, a deep learning-based approach is proposed by using the convolutional neural network. Specifically, the network model and parameters are well-designed based on the features of the channel impulse response and the mirror interference of IQI. To verify the designed model, it is first trained by simulated data under the off-line training and then used directly to recover the on-line transmitted data. The simulation results demonstrate that the proposed method shows excellent performance in processing OFDM signals under the case of IQI and it is more robust than traditional methods even without cyclic prefix.