Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α.

The transcription suppressor factor FBI-1 (the factor that binds to inducer of short transcripts-1) is an important regulator of hepatocellular carcinoma (HCC). In this work, the results showed that FBI-1 promoted the Warburg effect and enhances the resistance of hepatocellular carcinoma cells to molecular targeted agents. Knockdown of FBI-1 via its small-interfering RNA (siRNA) inhibited the ATP level, lactate productions, glucose uptake or lactate dehydrogenase (LDH) activation of HCC cells. Transfection of siFBI-1 also decreased the expression of the Warburg-effect-related factors: hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A (LDHA), or GLUT1, and the epithelial-mesenchymal transition-related factors, Vimentin or N-cadherin. The positive correlation between the expression of FBI-1 with HIF-1α, LDHA, or GLUT1 was confirmed in HCC tissues. Mechanistically, the miR-30c repressed the expression of HIF-1α by binding to the 3'-untranslated region (3'-UTR) of HIF-1α in a sequence-specific manner, and FBI-1 enhanced the expression of HIF-1α and HIF-1α pathway's activation by repressing the expression of miR. By modulating the miR-30c/HIF-1α, FBI-1 promoted the Warburg effect or the epithelial-mesenchymal transition of HCC cells and promoted the resistance of HCC cells to molecular targeted agents.

Long noncoding RNA MYLK-AS1 promotes growth and invasion of hepatocellular carcinoma through the EGFR/HER2-ERK1/2 signaling pathway.

The epidermal growth factor receptor (EGFR) family members EGFR and HER2 play pivotal roles in oncogenesis and tumor progression. Anticancer drugs targeting EGFR and HER2 have been developed. Long noncoding RNAs (lncRNAs) have been reported to regulate cancer development and progression through signaling pathways. However, lncRNAs that regulate EGFR and HER2 expression remain unknown. Here, we show that lncRNA myosin light chain kinase-antisense RNA 1 (MYLK-AS1) promotes EGFR and HER2 expression and activates their downstream signaling pathway. MYLK-AS1 increases hepatocellular carcinoma (HCC) cell proliferation, migration, and invasion in vitro. Consistently, MYLK-AS1 knockdown hinders tumor growth in vivo. Mechanistically, MYLK-AS1 enhances HCC cell proliferation, migration, and invasion through stimulating the EGFR/HER2-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. In addition, MYLK-AS1 is overexpressed in HCC patients and negatively correlated with HCC prognosis. Thus, MYLK-AS1 is an upstream regulator of EGFR/HER2, and acts as an oncogene, suggesting an additional target for cancer therapeutics.

Variations of mean sensitivity of tree rings in Asia and their influencing factors.

Mean sensitivity (MS) of tree ring is a key index representing the sensitivity of tree rings to climate. Understanding the variation of MS and its influencing factors at a large area is helpful to understand the interaction between tree growth and climate. We used 573 tree-ring width chronologies in Asia from the International Tree Ring Date Bank (ITRDB) to examine the variation of tree-ring sensitivity and potential influencing factors. The results showed that the MS of trees was high in the arid regions and cold regions. Precipitation was more important than temperature in diriving MS. Consistent with the pattern of up-down-up for precipitation, MS showed a down-up-down fluctuation with increasing altitude, indicating that precipitation affected by altitude was a key climate factor for the MS. MS had great difference due to different physiological traits among tree species. Light-adapted species, such as Juniperus przewalskii and Pinus gerardiana, had high MS due to drought tole-rance. Shade-adapted species, such as Picea and Abies, had low MS. Old trees may have high MS.

Effect of transarterial pulsed perfusion with heated saline on tumor vascular permeability in a rabbit VX2 liver tumor model.

PURPOSE: To evaluate the effect of transarterial pulsed perfusion with 60 °C saline on vascular permeability of tumor tissue, as well as its hepatic and renal toxicity, in a rabbit VX2 liver model. MATERIALS AND METHODS: VX2 carcinomas were grown in rabbit livers, forty male New Zealand white tumor-bearing rabbits were randomly divided into four groups, followed by transarterial perfusion with 37 °C saline 60 ml (n=10) (control 1 group), transarterial pulsed perfusion with 37 °C saline 60 ml (n=10) (control 2 group), transarterial continuous perfusion with 60 °C saline 60 ml (n=10) (TCP group), transarterial pulsed perfusion with 60 °C saline 60 ml (n=10) (TPP group), the duration of time for tumor tissues in the range 43-45 °C of the treated groups was measured with needle thermometer during perfusion. Vascular permeability was assessed using the extravasation of Evans blue (EB) dye in the tumor or normal liver tissues of the four groups separately, the tumor or normal liver tissues of the four groups were estimated by histopathologic examination, and hepatic and renal toxicity was evaluated by means of blood biochemical analysis. The vascular endothelial cells in the tumor were observed by transmission electron microscopy (TEM). RESULTS: The duration of time for tumor tissues in the range 43-45 °C of TPP group showed significantly longer than that of TCP group (12.3±3.3 min vs. 5.7±2.5 min) (P<0.01). After perfusion, the EB content of tumor tissue in TPP group showed significantly higher than that in TCP group (15.21±0.94 µg/100 mg vs. 10.71±0.84 µg/100 mg) (P<0.01), and also showed significantly higher than that in the two control group (3.42±0.87 µg/100 mg, 3.57±0.64 µg/100 mg) (P<0.01). Blood chemical analysis indicating there was an increase (P<0.05) in the serum ALT, AST levels in the two heated perfusion groups at 1, 2, 4, 8 h after infusion when compared to that in the two control group, but there was no significant difference in the serum ALT, AST levels among the four groups at 24 h after perfusion (P>0.05), and there was no significant difference in the serum BUN, Cr levels among the four groups at 1, 2, 4, 8, 24 h after perfusion. Observed by hematoxylin and eosin staining, there were no obvious signs of tissue destruction in liver tissue and tumor tissue. TEM indicating the endothelial cell gap was broadened and the endothelial cells' microvillus was decreased after heated perfusion. CONCLUSIONS: The vascular permeability of the rabbit VX2 tumor was significantly increased after transarterial pulsed perfusion with 60°C saline without significant increase in hepatic and renal toxicity.