UTMD inhibits pancreatic cancer growth and metastasis by inducing macrophage polarization and vessel normalization.

Pancreatic cancer (PaCa) is a hypovascular type of tumor and is not very responsive to conventional chemotherapy due to the problem of low drug accumulation. Recent advancements in ultrasound targeted microbubble destruction (UTMD) have improved drug delivery into target tissues. UTMD operates via microbubble interaction with vascular endothelial cells; however, the molecular mechanism and interrelationship in the PaCa microenvironment remain enigmatic. Tumor-associated macrophages (TAMs) have different phenotypes and regulate tumorigenesis. Using a PaCa orthotopic model, we established that UTMD improved chemotherapy by redirecting TAM polarization from M2 macrophages to tumor-inhibiting M1 macrophages, remodeling vessel normalization, and inducing anti-tumor immune responses. Tumor vascular maturity and function were also improved, and an insignificant change in vascular density resulting in enhanced blood perfusion and inhibited tumor growth and metastasis were observed. Therefore, this research unveils the crucial role of TAM polarization on UTMD-induced tumor vessel normalization and inhibition of tumor progression. These findings offer a novel insight into UTMD-mediated drug delivery for anti-tumor and anti-angiogenic treatment.

TCL1A acts as a tumour suppressor by modulating gastric cancer autophagy via miR-181a-5p-TCL1A-Akt/mTOR-c-MYC loop.

Gastric cancer is the third most commonly cause of tumour-related death worldwide and one of the most prevalent malignancies in China. TCL1A, TCL1 family Akt coactivator A, can active Akt/mTOR pathway and regulate the autophagy. However, the action of TCL1A in gastric cancer is not well understood. The present study is investigating the mechanism of action of TCL1A in gastric cancer. TCL1A was lowly expressed in gastric cancer tissues. Subsequent experiments demonstrated that miR-181a-5p can regulate c-MYC through the TCL1A-Akt/mTOR pathway and c-MYC can in turn affect the expression of miR-181a-5p, thus confirming the existence of the miR-181a-5p-TCL1A-Akt/mTOR-c-MYC loop. Flow cytometric apoptosis assay and mRFP-eGFP-LC3 autophagy assay demonstrated that both miR-181a-5p and TCL1A can affect autophagy and apoptosis of gastric cancer cells through the loop. In vivo experiments confirmed that TCL1A can affect the proliferation of gastric cancer. These results illustrate that TCL1A can exert tumour suppressive effects and affect gastric cancer autophagy and progression via the miR-181a-5p-TCL1A-Akt/mTOR-c-MYC loop, which could be a potential therapeutic target for gastric cancer.

A Genomic Instability-Related Long Noncoding RNA Signature for Predicting Hepatocellular Carcinoma Prognosis.

Background: Long noncoding RNAs (lncRNAs) are found to be novel biomarkers for hepatocellular carcinoma (HCC) and play an important role in tumor progression. We established a genomic instability-related long noncoding RNA signature (GIlncSig) as an independent prognosis factor and also investigated its impact on prognosis significance. Method: Somatic mutation profiles, clinical characteristics, and RNA sequencing data were obtained from The Cancer Genome Atlas (TCGA) database. Lasso regression was used to construct GIlncSig. KEGG was used to identify the possible biological pathways. ESTIMATE and CIBERSORT algorithms were used to calculate the immune microenvironment scores and proportion of immune cells in HCC patients. The expression of LINC00501 was conducted by qRT-PCR. Cell proliferation was measured by EdU, CCK-8, and colony formation assay, and cell migration and invasion ability were measured by wound healing and transwell assay. Results: 135 genomic instability-related lncRNAs were identified, and GIlncSig was constructed using 13 independent lncRNAs with significant prognosis values. Based on the GIlncSig, high-risk group had worse clinical outcomes than low-risk group, while high-risk group also had higher UBQLN4, KRAS, ARID1A, and PIK3CA expression. Moreover, the efficiency of GIlncSig combining single-gene mutation was higher than single-gene mutation alone such as TP53. The results of CIBERSORT and ESTIMATE showed that GS group and GU group had significantly different immune infiltration. In addition, LINC00501 was identified as a potential biomarker in HCC with strong relationship with clinical characteristics. In vitro assays validated that LINC00501 promoted proliferation and migration of HCC cell lines. Conclusion: Our results showed that GIlncSig serves as a potential independent prognosis factor to predict HCC patients' prognosis for exploring potential mechanism and therapy strategy. Besides, LINC00501 plays an important role in the progression of HCC, which may be a potential therapy target.

Global burden of primary liver cancer by five etiologies and global prediction by 2035 based on global burden of disease study 2019.

BACKGROUND: Using data from the global burden of disease (GBD) between 1990 and 2019 to report the leading etiological factors and hazards for liver cancer by HBV (LCHB), HCV (LCHC), alcoholic use (LCAL), NASH (LCNA), and other causes (LCOT). METHOD: The estimated annual percentage change (EAPC) and age-standardized incidence rate (ASR) in different districts, sex, and age are used to quantify the change of etiologies of liver cancer. Age-period-cohort models were performed to predict the primary liver cancer incidence and case numbers. RESULTS: Based on the GBD database of the whole world for the five etiologies of liver cancer in 2019, the percentage of incidence of LCAL, LCHB, LCHC, LCNA, and LCOT are 18.4%, 41%, 28.5%, 6.8%, and 5.3%, respectively. Fiver etiologies of liver cancer show gender differences, with LCHB and LCAL being more prevalent in men, and LCHC, LCNA being more prevalent in women. Besides, live cancer of males is because of alcohol using and smoking, while the reason of liver cancer of females is drug use, high BMI and high fasting plasma glucose. Interestingly, the incidence of LCHC in women over 85 years old, LCNA in women over 75 years old, and LCOT in women over 75 years old were all higher than that in men. According to the future prediction, the incidence rate of liver cancer itself, as well as the five causes of liver cancer, tends to decrease gradually after 2019, while the incidence rate of LCNA in males will continue to increase until 2025. CONCLUSIONS: The incidence of liver cancer has been increasing and its major causes vary considerably at global, regional, or national levels, also vary by gender and age group.