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Sorafenib is one a first-line therapeutic drugs for advanced hepatocellular carcinoma (HCC). However, only 30% of patients benefit from sorafenib due to drug resistance. We and other groups have revealed that nuclear factor I B (NFIB) regulates liver regeneration and carcinogenesis, but its role in drug resistance is poorly known. We found that NFIB was more upregulated in sorafenib-resistant SMMC-7721 cells compared to parental cells. NFIB knockdown not only sensitized drug-resistant cells to sorafenib but also inhibited the proliferation and invasion of these cells. Meanwhile, NFIB promoted the proliferation and invasion of HCC cells in vitro and facilitated tumor growth and metastasis in vivo. Knocking down NFIB synergetically inhibited tumor growth with sorafenib. Mechanically, gene expression profiling and subsequent verification experiments proved that NFIB could bind with the promoter region of a complex I inhibitor NDUFA4L2 and promote its transcription. Transcriptional upregulation of NDUFA4L2 by NFIB could thus inhibit the sorafenib-induced reactive oxygen species accumulation. Finally, we found that NFIB was highly expressed in HCC tissues, and high NFIB expression level was associated with macrovascular invasion, advanced tumor stage, and poor prognosis of HCC patients (n = 156). In summary, we demonstrated that NFIB could transcriptionally upregulate NDUFA4L2 to enhance both intrinsic and acquired sorafenib resistance of HCC cells by reducing reactive oxygen species induction.

Metabolic reprogramming is a hallmark of cancer, including hepatocellular carcinoma (HCC). However, its role in HCC remains to be elucidated. Herein, we identified GTP cyclohydrolase 1 (GCH1), the first rate-limiting enzyme in tetrahydrobiopterin (BH4) de novo biosynthesis, as a novel metabolic regulator of HCC. GCH1 was frequently down-regulated in HCC tissues and cell lines by promoter methylation. Low GCH1 expression was associated with larger tumor size, increased tumor number, and worse prognosis in two independent cohorts of HCC patients. Functionally, GCH1 silencing promoted HCC growth in vitro and in vivo, while GCH1 overexpression exerted an opposite effect. The metabolite BH4 inhibited HCC growth in vitro and in vivo. GCH1 silencing exerted its growth-promoting effect through directly inhibiting BH4 de novo biosynthesis. Mechanistically, GCH1 silencing activated ASK1/p38 signaling; pharmacological or genetic inhibition of ASK1 or p38 abolished GCH1 silencing-induced growth-promoting effect. Further mechanistic studies found that GCH1 silencing-induced BH4 reduction resulted in an increase of intracellular superoxide anion levels in a dose-dependent manner, which mediated the activation of ASK1/p38 signaling. Collectively, our study reveals that epigenetic silencing of GCH1 promotes HCC growth by activating superoxide anion-mediated ASK1/p38 signaling via inhibiting BH4 de novo biosynthesis, suggesting that targeting GCH1/BH4 pathway may be a promising therapeutic strategy to combat HCC.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and currently the second leading cause of cancer-related mortality worldwide. One recent study reported that lncRNA-LALR1 promotes liver regeneration, the role and underlying mechanisms of lncRNA-LALR1 in HCC remain largely unknown. In this study, we demonstrated that lncRNA-LALR1 was significantly upregulated in HCC tissues compared with adjacent tissues and high expression of lncRNA-LALR1 was associated with advanced TNM stage, poor differentiation, and distant metastasis. RNA Fluorescence in situ hybridization analysis showed lncRNA-LALR1 was expressed not only in cytoplasm but also in nucleolus. Knockdown of lncRNA-LALR1 obviously inhibited HCC cells growth and invasion in vivo and in vitro. Besides, transcriptomic analysis and subsequent confirmation revealed that lncRNA-LALR1 upregulated small nucleolar RNA SNORD72 via binding with SNORD72 and stabilized ID2 mRNA. SNORD72 was overexpressed in HCC tissues and enhanced HCC cells proliferation, colony formation and invasion. Overexpression of SNORD72 could also stabilize ID2 mRNA and rescue the inhibitory effect of silencing lncRNA-LALR1. In conclusion, lncRNA-LALR1 is highly expressed in HCC and promotes tumor growth and invasion by upregulating SNORD72 to stabilize ID2 mRNA, implying that lncRNA-LALR1 might be a novel target for intervention of HCC.

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Acidic microenvironment, namely acidosis, is closely related to cancer development and progression, but the regulatory mechanism remains to be elucidated. Methods We generated acidosis-adapted PDAC cells (PANC-1 and SW1990) by continuously culturing under pH 6.5 medium. Metabonomic assay (LC-MS and LC-MS) was used to detect the metabolites. Transcriptomic microarray was applied to reveal the gene expression profile. The in vivo metastatic potential was assessed by tail vein injection. Wound healing assay and transwell assay were applied to evaluate cell migration and invasion capacity. CCK8 and colony formation were performed to determine cell proliferation. Flow cytometry was used to test cell cycle and apoptosis. Results These acidosis-adapted PDAC cells had stronger invasion and migration ability, accompanied by increased EMT markers expression. In addition, the proliferation rate of acidosis-adapted PDAC cells increased while apoptosis decreased under acidic medium. Metabonomic analysis showed that the glycolysis and AMP was decreased, and ATP was increased in acidosis-adapted cells. The metabolic shift led to the inactivation of AMPK. Transcriptomic analysis revealed that the differentially expressed genes in acid-adapted cells were enriched in extracellular matrix modification, Hippo signaling and others. MMP1, a matrix metalloproteinase, was the most upregulated gene in acidosis-adapted cells, mediated by the YAP/TAZ pathway. Knockdown of MMP1 significantly reduced invasion and metastasis capacity of acidosis-adapted cells. The AMPK activator MK8722 could reduce both YAP and MMP1 level in acidosis-adapted PDAC cells. Conclusion Altogether, the present study showed that the metabolic reprogramming towards elevated ATP production promotes invasion and metastasis of acidosis-adapted PDAC cells via depressing AMPK/Hippo signaling, thus upregulating MMP1.

The acidic extracellular microenvironment, namely acidosis, is a biochemical hallmark of solid tumors. However, the tumorigenicity, metastatic potential, gene expression profile and chromatin accessibility of acidosis-adapted colorectal cancer cells remain unknown. The colorectal cancer cell SW620 was cultured in acidic medium (pH 6.5) for more than 3 months to be acidosis-adapted (SW620-AA). In comparison to parental cells, SW620-AA cells exhibit enhanced tumorigenicity and liver metastatic potential in vivo. Following mRNA and lncRNA expression profiling, we validated that OLMF1, NFIB, SMAD9, DGKB are upregulated, while SESN2, MAP1B, UTRN, PCDH19, IL18, LMO2, CNKSR3, GXYLT2 are downregulated in SW620-AA cells. The differentially expressed mRNAs were significantly enriched in DNA remodeling-associated pathways including HDACs deacetylate histones, SIRT1 pathway, DNA methylation, DNA bending complex, and RNA polymerase 1 chain elongation. Finally, chromatin accessibility evaluation by ATAC-sequencing revealed that the differentially opened peaks were enriched in pathways such as small cell lung cancer, pathways in cancer, ErbB signaling, endometrial cancer, and chronic myeloid leukemia, which were mainly distributed in intergenic regions and introns. These results suggest that the chromatin accessibility changes are correlated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells.

With a large amount of tyres being discarded every year, the question of how to manage the end-of-life tyres (ELTs) has become a serious issue. Thus this study identifies different driving forces for this management and the most possible scenarios for the future management of ELTs. The study also compares the business as usual model with a waste hierarchy model to explore the possibilities for optimizing management of ELTs through cascading. This study collects opinions about the driving forces of ELT management from 29 experts working in the area. Important driving forces identified were: price of substitute products, recycled materials’ market, environmental legislation, and technology. This study also surveys 23 experts in the tyre area about the most possible scenarios for ELTs in 2020. One of the more believed in futures was: “Due to increasingly limited fossil fuels and a rise of sustainability awareness, applications for ELTs are growing both in material and energy recycling.” This suggests that a shift toward an equal recycling situation of ELTs among material and energy might be likely to happen by 2020. Based on the most possible scenario for ELTs in 2020, a comparison between waste hierarchy model and business as usual model has been performed. The result shows that the (cascading) waste hierarchy model would likely create more environmental benefits than business as usual model. This is done though the saving and cycling of more materials from energy recovery into material recycling.