Copper metabolism-related risk score identifies hepatocellular carcinoma subtypes and SLC27A5 as a potential regulator of cuproptosis.

AIMS: Dysregulated copper metabolism has been noticed in many types of cancer including hepatocellular carcinoma (HCC); however, a comprehensive understanding about this dysregulation still remains unclear in HCC. METHODS: A set of bioinformatic tools was integrated to analyze the expression and prognostic significance of copper metabolism-related genes. A related risk score, termed as CMscore, was developed via univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression. Pathway enrichment analyses and tumor immune cell infiltration were further investigated in CMscore stratified HCC patients. Weighted correlation network analysis (WGCNA) was used to identify potential regulator of cuproptosis. RESULTS: Copper metabolism was dysregulated in HCC. HCC patients in the high-CMscore group showed a significantly lower overall survival (OS) and enriched in most cancer-related pathways. Besides, HCC patients with high CMscore had higher expression of pro-tumor immune infiltrates and immune checkpoints. Moreover, cancer patients with high CMscore from two large cohorts exhibited significantly prolonged survival time after immunotherapy. WGCNA and subsequently correlation analysis revealed that SLC27A5 might be a potential regulator of cuproptosis in HCC. In vitro experiments revealed that SLC27A5 inhibited cell proliferation and migration of HCC cells and could upregulate FDX1, the key regulator of cuproptosis. SIGNIFICANCE: The CMscore is helpful in clustering HCC patients with distinct prognosis, gene mutation signatures, and sensitivity to immunotherapy. SLC27A5 might serve as a potential target in the induction of cuproptosis in HCC.

Advances in MUC1 resistance to chemotherapy in pancreatic cancer.

The incidence of pancreatic cancer (PC), a highly fatal malignancy, is increasing every year. Chemotherapy is an important treatment for it in addition to surgery, yet most patients become resistant to chemotherapeutic agents within a few weeks of treatment initiation.​ MUC1 is a highly glycosylated transmembrane protein, and studies have shown that aberrantly glycosylated overexpression of MUC1 is involved in regulating the biology of chemoresistance in cancer cells. This article summarizes the mechanism of MUC1 in PC chemoresistance and reviews MUC1-based targeted therapies.

Apatinib plus drug-eluting bead transarterial chemoembolization as bridging therapy to surgical resection displays an acceptable efficacy and safety profile in hepatocellular carcinoma patients.

BACKGROUND: Apatinib exhibits a synergistic effect with transarterial chemoembolization (TACE) by inhibiting TACE-induced neoangiogenic reaction in hepatocellular carcinoma (HCC) patients. But apatinib plus drug-eluting bead TACE (DEB-TACE) is rarely reported as a bridging therapy to surgery. This study aimed to evaluate the efficacy and safety of apatinib plus DEB-TACE as a bridge to surgical resection in intermediate-stage HCC patients. MATERIALS AND METHODS: Thirty-one intermediate-stage HCC patients who received apatinib plus DEB-TACE as a bridging therapy to surgery were enrolled. After the bridging therapy, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and objective response rate (ORR) were evaluated; meanwhile, relapse-free survival (RFS) and overall survival (OS) were determined. RESULTS: After the bridging therapy, three (9.7%), twenty one (67.7%), seven (22.6%), and twenty four (77.4%) patients achieved CR, PR, SD, and ORR, respectively; besides, PD did not occur. The successful downstaging rate was 18 (58.1%). The median (95% confidence interval [CI]) accumulating RFS was 33.0 (19.6 - 46.6) months. Besides, the median (95% CI) accumulating OS was 37.0 (24.8 - 49.2) months. HCC patients with successful downstaging showed a higher accumulating RFS rate ( P = 0.038) and similar accumulating OS rate ( P = 0.073) compared to those without successful downstaging. The overall incidence of adverse events was relatively low. Besides, all the adverse events were mild and controllable. The most frequent adverse events included pain (14 [45.2%]) and fever (9 [29.0%]). CONCLUSION: Apatinib plus DEB-TACE as a bridging therapy to surgical resection displays good efficacy and safety profile in intermediate-stage HCC patients.

Mapping of lymph node dissection determined by the epicenter location and tumor extension for esophagogastric junction carcinoma.

Backgrounds: Previous studies identified the extent of lymph node dissection for esophagogastric junction (EGJ) carcinoma based on the metastatic incidence. The study aimed to determine the optimal extent and priority of lymphadenectomy based on the therapeutic efficacy from each station. Methods: The studies on the lymph node metastasis (LNM) and therapeutic efficacy index (EI) for EGJ carcinomas were identified until April 2022. The obligatory stations with the LNM rates over 5% and therapeutic EI exceeding 2% should be routinely resected for D2 dissection, whereas the optional stations with EI between 0.5% and 2% should be resected for D3 dissection in selective cases. Results: The survey yielded 16 eligible articles including 6,350 patients with EGJ carcinoma. The metastatic rates exceeded 5% at no. 1, 2, 3, 7, 9, 11p, and 110 stations and were less than 5% in abdominal no. 4sa~6, 8a, 10, 11d, 12a, and 16a2/b1 and mediastinal no. 105~112 stations. Consequently, obligatory stations with EI over 2% were largely determined by the epicenter location and located at the upper perigastric, lower mediastinal, and suprapancreatic zones, corresponding to those with rates of LNM over 5%. Consistent with the LNM rates less than 5%, the optional stations with EI between 0.5% and 2% were largely dependent on the degree of tumor extension toward the lower perigastric, splenic hilar (grecurvature), para-aortic (less curvature of the cardia), and middle or upper mediastinal zones. Conclusions: The obligatory stations can be resected as an "envelope-like" wrap by transhiatal proximal gastrectomy with lower esophagectomy, whereas the optional stations for dissection are indicated by the tumor extension. The extended gastrectomy is required for the lower perigastric in the stomach-predominant tumor with gastric involvement exceeding 5.0 cm, para-aortic dissection in the less curvature-predominant tumor and splenic hilar dissection in the grecurvature-predominant tumor whereas transthoracic subtotal esophagectomy is required for complete mediastinal dissection and adequate negative margin in the esophagus-predominant tumor with esophageal invasion exceeding 3.0 cm.

The Role of lncRNA PVT1 and hsa-miR-30a-3p in the Development of Gastric Cancer.

OBJECTIVE: Aberrantly expressed lncRNAs have been detected in gastric cancer (GC). LncRNA PVT1 is involved in numerous types of human malignant tumor. In this project, we demonstrated the relationship between PVT1 and Myc and tested the function of PVT1 and hsa-miR-30a-3p in the tumorigenesis of GC. METHODS: For experimental study, RNA-Seq datasets and equivalent clinical data for 367 samples were achieved from The Cancer Genome Atlas (TCGA)-STAD datasets. The online software clusterProfiler was used to perform Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional enrichment. The co-expression of YY1, PVT1, and Myc genes was evaluated by determining the Pearson correlation coefficients. Potential competing endogenous RNAs of PVT1-miRNA-Myc were predicted by the Cytoscape tool and Kaplan- Meier curves were generated for YY1, PVT1, and Myc genes. For clinical study, Human GC samples were taken from 26 pairs of GC tissue (GCT) and para-tumor tissue (PT, 5 cm from the edge of the tumor) in which no patient had previously undergone preoperative adjuvant chemotherapy or radiotherapy. RESULTS: For experimental study, a total of 1144 differential expression genes (DEGs) were identified consisting of 731 up-regulated genes and 413 down-regulated genes. DEGs were Myc, YY1, and PVT1 and PVT1 was significantly different (adj. P=1.11E-11). The correlation coefficient between PVT1 and Myc was 0.42. A ceRNA network model suggested the hsa-miR-30a-3p was interacted between PVT1 and Myc, playing the role of information transmission. Survival analysis of these genes suggested that lncRNA PVT1 might influence the GC case survival (p=0.06). PVT1 expression was upregulated in human gastric cancer tissues and its relative PVT1 expression of PT was increased two fold compared to GCT. The expressions of PVT1 from the tumor tissues were significantly upregulated in GCT. CONCLUSION: These discoveries imply that lncRNA PVT1 and hsa-miR-30a-3p has a responsibility in the GC development. Therefore, targeting PVT1 or/and hsa-miR-30a-3p as a strategy for gastric cancer should be explored.

Molecular imaging and deep learning analysis of uMUC1 expression in response to chemotherapy in an orthotopic model of ovarian cancer.

Artificial Intelligence (AI) algorithms including deep learning have recently demonstrated remarkable progress in image-recognition tasks. Here, we utilized AI for monitoring the expression of underglycosylated mucin 1 (uMUC1) tumor antigen, a biomarker for ovarian cancer progression and response to therapy, using contrast-enhanced in vivo imaging. This was done using a dual-modal (magnetic resonance and near infrared optical imaging) uMUC1-specific probe (termed MN-EPPT) consisted of iron-oxide magnetic nanoparticles (MN) conjugated to a uMUC1-specific peptide (EPPT) and labeled with a near-infrared fluorescent dye, Cy5.5. In vitro studies performed in uMUC1-expressing human ovarian cancer cell line SKOV3/Luc and control uMUC1low ES-2 cells showed preferential uptake on the probe by the high expressor (n = 3, p < .05). A decrease in MN-EPPT uptake by SKOV3/Luc cells in vitro due to uMUC1 downregulation after docetaxel therapy was paralleled by in vivo imaging studies that showed a reduction in probe accumulation in the docetaxel treated group (n = 5, p < .05). The imaging data were analyzed using deep learning-enabled segmentation and quantification of the tumor region of interest (ROI) from raw input MRI sequences by applying AI algorithms including a blend of Convolutional Neural Networks (CNN) and Fully Connected Neural Networks. We believe that the algorithms used in this study have the potential to improve studying and monitoring cancer progression, amongst other diseases.

Single nucleotide polymorphism rs2555639 in 15-PGDH and colorectal cancer metastasis.

PURPOSE: To investigate the correlation between metastasis of colon cancer and the single nucleotide polymorphism (SNP) rs2555639 in nicotinamide adenine dinucleotide (NAD)+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (rs2555639). METHODS: We investigated the genotyping of peripheral blood genomic DNA in patients using the TaqMan probe method. The relationship between the genotype of 15-PGDH (rs2555639) and metastasis of colon cancer was analyzed. RESULTS: We noticed that rs2555639 TT polymorphism was significantly correlated with the susceptibility to colon cancer metastasis. Also, in the stratified analysis, we found similar results. CONCLUSION: Our data suggested that the rs2555639 T allele is associated with increased risk of metastasis of colon cancer, which can be used as an indicator for colon cancer metastasis.

Retracted Article: MiR-182-5p and miR-96-5p increased hepatocellular carcinoma cell mobility, proliferation and cisplatin resistance partially by targeting RND3.

We investigated whether miR-182-5p or miR-96-5p could increase hepatocellular carcinoma (HCC) development by targeting Rho Family GTPase 3 (RND3) gene expression. The expression levels of miR-182-5p, miR-96-5p and mRNA/protein of RND3 in non-HCC liver tissue, HCC tissue and adjacent tissue specimens were evaluated by RT-qPCR and western blot. Patient-derived HCC cell culture was established, and miR-182-5p or miR-96-5p agomir or antagomir treatment was performed to mimic the overexpression or knockdown of the two miRNAs. HCC cell mobility in vitro was monitored by trans-well migration and invasion assay, while HCC cell growth in vitro was evaluated by cell viability, proliferation and apoptosis assay. HCC cell apoptosis was further investigated by caspase-3/-8/-9 activity assay. MiR-182-5p and miR-96-5p were significantly upregulated in HCC tissue specimens compared with non-HCC or adjacent tissue specimens, inversely correlating to RND3 mRNA expression level. Treatment with miR-182-5p or miR-96-5p agomir significantly reduced RND3 mRNA/protein expression level in HCC cells. MiR-182-5p- or miR-96-5p-targeting RND3 mRNA was verified by luciferase reporter assay and AGO2-RNA immunoprecipitation assay. MiR-182-5p or miR-96-5p agomir treatment significantly rescued HCC cell migration and invasion in vitro that were repressed by RND3 overexpression, during which ROCK1 and ROCK2 inhibition were involved. MiR-182-5p or miR-96-5p agomir treatment also increased HCC cell proliferation and cisplatin resistance in vitro, which could be antagonized by RND3 overexpression or ROCK inhibition. Thus, miR-182-5p and miR-96-5p increased HCC cell mobility, proliferation and cisplatin resistance in vitro partially by targeting RND3.