Elevated expression of HIGD1A drives hepatocellular carcinoma progression by regulating polyamine metabolism through c-Myc-ODC1 nexus.

BACKGROUND: Hypoxia contributes to cancer progression through various molecular mechanisms and hepatocellular carcinoma (HCC) is one of the most hypoxic malignancies. Hypoxia-inducible gene domain protein-1a (HIGD1A) is typically induced via epigenetic regulation and promotes tumor cell survival during hypoxia. However, the role of HIGD1A in HCC remains unknown. METHODS: HIGD1A expression was determined in 24 pairs of human HCC samples and para-tumorous tissues. Loss-of-function experiments were conducted both in vivo and in vitro to explore the role of HIGD1A in HCC proliferation and metastasis. RESULTS: Increased HIGD1A expression was found in HCC tissues and cell lines, which was induced by hypoxia or low-glucose condition. Moreover, HIGD1A knockdown in HCC cells arrested the cell cycle at the G2/M phase and promoted hypoxia-induced cell apoptosis, resulting in great inhibition of cell proliferation, migration, and invasion, as well as tumor xenograft formation. Interestingly, these anti-tumor effects were not observed in normal hepatocyte cell line L02. Further, HIGD1A knockdown suppressed the expression of ornithine decarboxylase 1 (ODC1), a rate-limiting enzyme of polyamine metabolism under c-Myc regulation. HIGD1A was found to bind with the c-Myc promoter region, and its knockdown decreased the levels of polyamine metabolites. Consistently, the inhibitory effect on HCC phenotype by HIGD1A silencing could be reversed by overexpression of c-Myc or supplementation of polyamines. CONCLUSIONS: Our results demonstrated that HIGD1A activated c-Myc-ODC1 nexus to regulate polyamine synthesis and to promote HCC survival and malignant phenotype, implying that HIGD1A might represent a novel therapeutic target for HCC.

Targeting NAD+ metabolism of hepatocellular carcinoma cells by lenvatinib promotes M2 macrophages reverse polarization, suppressing the HCC progression.

BACKGROUND: Lowered nicotinamide adenine dinucleotide (NAD+) levels in tumor cells drive tumor hyperprogression during immunotherapy, and its restoration activates immune cells. However, the effect of lenvatinib, a first-line treatment for unresectable hepatocellular carcinoma (HCC), on NAD+ metabolism in HCC cells, and the metabolite crosstalk between HCC and immune cells after targeting NAD+ metabolism of HCC cells remain unelucidated. METHODS: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and ultra-high-performance liquid chromatography multiple reaction monitoring-mass spectrometry (UHPLC-MRM-MS) were used to detect and validate differential metabolites. RNA sequencing was used to explore mRNA expression in macrophages and HCC cells. HCC mouse models were used to validate the effects of lenvatinib on immune cells and NAD+ metabolism. The macrophage properties were elucidated using cell proliferation, apoptosis, and co-culture assays. In silico structural analysis and interaction assays were used to determine whether lenvatinib targets tet methylcytosine dioxygenase 2 (TET2). Flow cytometry was performed to assess changes in immune cells. RESULTS: Lenvatinib targeted TET2 to synthesize and increase NAD+ levels, thereby inhibiting decomposition in HCC cells. NAD+ salvage increased lenvatinib-induced apoptosis of HCC cells. Lenvatinib also induced CD8+ T cells and M1 macrophages infiltration in vivo. And lenvatinib suppressed niacinamide, 5-Hydroxy-L-tryptophan and quinoline secretion of HCC cells, and increased hypoxanthine secretion, which contributed to proliferation, migration and polarization function of macrophages. Consequently, lenvatinib targeted NAD+ metabolism and elevated HCC-derived hypoxanthine to enhance the macrophages polarization from M2 to M1. Glycosaminoglycan binding disorder and positive regulation of cytosolic calcium ion concentration were characteristic features of the reverse polarization. CONCLUSIONS: Targeting HCC cells NAD+ metabolism by lenvatinib-TET2 pathway drives metabolite crosstalk, leading to M2 macrophages reverse polarization, thereby suppressing HCC progression. Collectively, these novel insights highlight the role of lenvatinib or its combination therapies as promising therapeutic alternatives for HCC patients with low NAD+ levels or high TET2 levels.

A Truck-Borne System Based on Cold Atom Gravimeter for Measuring the Absolute Gravity in the Field.

The cold atom gravimeter (CAG) has proven to be a powerful quantum sensor for the high-precision measurement of gravity field, which can work stably for a long time in the laboratory. However, most CAGs cannot operate in the field due to their complex structure, large volume and poor environmental adaptability. In this paper, a home-made, miniaturized CAG is developed and a truck-borne system based on it is integrated to measure the absolute gravity in the field. The measurement performance of this system is evaluated by applying it to measurements of the gravity field around the Xianlin reservoir in Hangzhou City of China. The internal and external coincidence accuracies of this measurement system were demonstrated to be 35.4 µGal and 76.7 µGal, respectively. Furthermore, the theoretical values of the measured eight points are calculated by using a forward modeling of a local high-resolution digital elevation model, and the calculated values are found to be in good agreement with the measured values. The results of this paper show that this home-made, truck-borne CAG system is reliable, and it is expected to improve the efficiency of gravity surveying in the field.

Real-life impact of tenofovir disoproxil fumarate and entecavir therapy on lipid profile, glucose, and uric acid in chronic hepatitis B patients.

The impact of long-term nucleos(t)ide analogs treatment on host metabolism is a concern. Hence, we conducted this study to compare the effect of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on metabolic parameters among chronic hepatitis B (CHB) patients. In this real-life retrospective study, 2030 CHB outpatients treated with ETV or TDF at Nanfang Hospital, China, were included. For treatment-naïve patients, pretreatment and semiannual metabolic parameters were collected. For treatment-experienced patients, metabolic parameters were collected at the first visit. Propensity score matching (PSM) was used to balance the effects of potential confounding factors. Among 122 treatment-naïve patients and 1908 treatment-experienced patients, ETV-treated patients were older with a higher percentage of metabolic syndrome. After PSM, the characteristics were comparable between the two groups. For treatment-naïve patients, four lipid parameters, including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein, and triglyceride levels showed a decreasing trend during the 42-month TDF treatment, while they remained relatively stable or increased during ETV treatment. At Month 30, the levels of TC and LDL among TDF-treated patients were significantly lower than those among ETV-treated patients (TC: 4.7 mmol/L vs. 3.9 mmol/L, p = 0.004; LDL: 3.0 mmol/L vs. 2.4 mmol/L, p = 0.009). For treatment-experienced patients, we also observed lower levels of lipid parameters in patients with different durations of TDF treatment. The levels of glucose and uric acid were similar among ETV- and TDF-treated patients. TDF has a lipid-lowering effect in CHB patients, which provides a basis for the selection of antiviral drugs for aging CHB patients.

Small-Nanostructure-Size-Limited Phonon Transport within Composite Films Made of Single-Wall Carbon Nanotubes and Reduced Graphene Oxides.

Nanocarbon materials have been widely used for nanoelectronics and energy-related applications. In this work, composite films consisting of reduced graphene oxides (rGOs) and single-wall carbon nanotubes (SWCNTs) are synthesized and studied for their in-plane thermal conductivities. Different from pristine carbon nanotubes or graphene with decreased thermal conductivities above 300 K, the in-plane thermal conductivities of these composite films are found to follow the trend of the specific heat of graphene from 100 to 400 K, i.e., monotonously increasing at elevated temperatures. Such a trend can often be found within amorphous solids but has seldom been observed for nanocarbon. This unique temperature dependence of thermal conductivities is attributed to the largely restricted phonon mean free paths within the graphene sheets that mainly contribute to the in-plane thermal transport. The highest in-plane thermal conductivity among samples with different synthesis conditions is 62.8 W/(m·K) at 300 K. Such a high thermal conductivity, combined with its unique temperature dependency, can be ideal for applications such as flexible film-like thermal diodes based on the junction between two materials with a large contrast for their temperature dependence of the thermal conductivity.