TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.

Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet, cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall shed insight into cancer progression and benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. It remains unclear whether and how TFE3 responds to glucose starvation. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3-SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer.

The P53-P21-RB1 pathway promotes BRD4 degradation in liver cancer through USP1.

Liver cancer is notoriously refractory to conventional therapeutics. Tumor progression is governed by the interplay between tumor-promoting genes and tumor-suppressor genes. BRD4, an acetyl lysine-binding protein, is overexpressed in many cancer types, which promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains incompletely understood. In addition, understanding the regulatory mechanism of BRD4 protein level will shed insight into BRD4-targeting therapeutics. In this study, we investigated the potential relation between BRD4 protein level and P53, the most frequently dysregulated tumor suppressor. By analyzing the TCGA datasets, we first identify a strong negative correlation between protein levels of P53 and BRD4 in liver cancer. Further investigation shows that P53 promotes BRD4 protein degradation. Mechanistically, P53 indirectly represses the transcription of USP1, a deubiquitinase, through the P21-RB1 axis. USP1 itself is also overexpressed in liver cancer and we show USP1 deubiquitinates BRD4 in vivo and in vitro, which increases BRD4 stability. With cell proliferation assays and xenograft model, we show the pro-tumor role of USP1 is partially mediated by BRD4. With functional transcriptomic analysis, we find the USP1-BRD4 axis upholds expression of a group of cancer-related genes. In summary, we identify a functional P53-P21-RB1-USP1-BRD4 axis in liver cancer.

Comparison of percutaneous balloon compression and microvascular decompression in the treatment of trigeminal neuralgia.

Objective: To compare the effect of percutaneous balloon compression (PBC) and microvascular decompression (MVD) in the treatment of trigeminal neuralgia (TN). Methods: Data of 98 patients with TN, admitted to Chenzhou First People's Hospital from May 2020 to May 2022, were retrospectively collected. Patients were divided into two groups based on the surgical method. A total of 53 patients treated with PBC comprised the PBC-group and 45 patients treated with MVD comprised the MVD-group. The immediate pain relief, long-term efficacy, surgical complications, and masticatory muscle strength of the two groups were compared and analyzed. Results: There was no significant difference in the immediate pain relief and long-term e efficacy, between the two groups (P>0.05). Complication rate in the PBC-group was significantly lower than that in the MVD-group (3.77% vs 17.78%, P<0.05). Medical records within 14 days after the operation showed that the incidence of facial numbness and masticatory muscle weakness in the PBC-group were 37.74% and 28.30% respectively, significantly higher than those in MVD-group (4.44% and 2.22%) (P<0.05). These symptoms gradually improved three months after the surgery, and were almost completely resolved after six months. Conclusions: Compared with MVD, PBC has the same effect in the treatment of TN. PBC is a minimally invasive, safe, and effective method with a low complication rate. Although masticatory muscle strength is slightly impacted by PBC, it gradually recovers within six months after the operation.

Predictive value of monocyte to high-density lipoprotein cholesterol ratio and tumor markers in colorectal cancer and their relationship with clinicopathological characteristics.

OBJECTIVE: To evaluate the predictive value of monocyte (M) to high-density lipoprotein cholesterol (HDL-C) ratio (MHR) and tumor markers in colorectal cancer (CRC) and their correlation with clinicopathological characteristics. METHODS: Hematology test data and medical records of 202 CRC patients and 201 healthy subjects were collected retrospectively. The diagnostic efficacy of MHR was evaluated using receiver operating characteristic (ROC) curves and risk factors for CRC were analyzed by multivariate logistic regression. RESULTS: CRC patients had significantly higher M, MHR, carcinoembryonic antigen (CEA), and carbohydrate antigen 199 (CA199) levels, but significantly lower HDL-C levels than healthy controls (all P < 0.05). Additionally, MHR was positively correlated with tumor differentiation in CRC patients (P = 0.049); CEA and CA199 levels in CRC patients increased with increased stage, lymph node metastasis and tumor size ≥ 5 cm (all P < 0.05). Furthermore, high levels of MHR, CA199 and CEA were independent risk factors for CRC. The area under ROC curve of MHR combined with CEA and CA199 was 0.882/0.869 for the diagnosis of CRC, respectively. CONCLUSION: This is the first study to explore the predictive value of MHR in CRC, and its continuous increase is an independent risk factor for CRC. MHR is a promising predictor for CRC progression along with CA199 and CEA.

[Isolation and multipotent differentiation of human decidua basalis-derived mesenchymal stem cells].

OBJECTIVE: To investigate the biological features of human decidua basalis-derived mesenchymal stem cells (PDB-MSCs) in vitro and identify their capacity of multilineage differentiation. METHODS: PDB-MSCs were harvested from the decidua basalis of term placental by enzymatic digestion and density gradient centrifugation, and the growth characteristics and morphological changes of the MSCs were observed by inverted microscope. The proliferative ability of the cells was assessed by Cell Counting Kit-8. The cell cycle and expressions of the surface markers (CD29, CD44, CD73, CD90, CD34, CD45, and CD14) of the MSCs were identified by flow cytometry. Multilineage differentiation capacity of the cells was tested by inducing their differentiation toward osteoblasts, adipocytes and chondroblasts in vitro. RESULTS: MSCs isolated from human decidua basalis of term placental exhibited a morphology similar to that of bone marrow-derived MSCs, and grew into colonies in in vitro culture, where the cells proliferated rapidly after passage with a cell doubling time of 2.21∓0.21 days. More than 70% of the cells stayed in the resting stage (G(0)/G(1)) and showed positivity for CD29, CD44, CD73 and CD90, but not for CD14, CD34 or CD45. After induction, the cells showed positive results of alizarin red staining, oil red O staining and Alcian blue staining. CONCLUSION: Human decidua basalis contains a rich source of MSCs, which can be easily isolated and cultured without affecting their capacity of multilineage differentiation. The PDB-MSCs may have the potential as a novel source of stem cells.

[Construction of a mouse pDsRed2-N1-SDF-1alpha eukaryotic expression vector and its expression in mouse bone marrow mesenchymal stem cells].

OBJECTIVE: To construct the eukaryotic expression vector pDsRed2-N1-SDF-1alpha and observe its expression in the mouse bone marrow mesenchymal stem cells. METHOD: SDF-1alpha gene sequence with XhoI, EcoRI restriction enzyme cutting site was amplified from the total RNA of mouse smooth muscle cells by reverse transcription-polymerase chain reaction (RT-PCR) and inserted into the eukaryotic expression vector pDsRed2-N1 encoding red fluorescent protein gene, and the insertion was verified by endonuclease digestion and DNA sequencing. Mouse bone marrow mesenchymal stem cells identified with immunofluorescence assay for vimentin expression were transfected with the constructed plasmid pDsRed2-N1-SDF-1alpha, and the expression of sdf-1alpha was detected using immunofluorescence assay. RESULTS: The DNA fragment amplified by PCR from the total RNA was identical to SDF-1alpha from the gene library, and an identical DNA fragment was also amplified from the recombinants. Sequence analysis confirmed the successful insertion of SDF-1alpha into the pDsRed2-N1 vector and the eukaryotic expression vector pDsRed2-N1-SDF-1alpha was successfully constructed. The cultured mouse bone marrow mesenchymal stem cells positive for vimentin protein showed SDF-1alpha expression 24 h after transfection with the recombinant vector. CONCLUSION: The pDsRed2-N1-SDF-1alpha eukaryotic expression vector constructed is capable of expression of SDF-1alpha fusion protein in the mouse bone marrow mesenchymal stem cells.