Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, whose initiation and development are driven by alterations in driver genes. In this study, we identified four driver genes (TP53, PTEN, CTNNB1, and KRAS) that show a high frequency of somatic mutations or copy number variations (CNVs) in patients with HCC. Four different spontaneous HCC mouse models were constructed to screen for changes in various kinase signaling pathways. The sgTrp53 + sgPten tumor upregulated mTOR and noncanonical nuclear factor-κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo. The JAK-signal transducer and activator of transcription (STAT) signaling was activated in Ctnnb1mut + sgPten tumor, the proliferation of which was strongly inhibited by napabucasin (a STAT3 inhibitor). Additionally, mTOR, cytoskeleton, and AMPK signaling were upregulated while rapamycin and ezrin inhibitors exerted potent antiproliferative effects in sgPten + KrasG12D tumor. We found that JAK-STAT, MAPK, and cytoskeleton signaling were activated in sgTrp53 + KrasG12D tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC who had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor.

Bremsstrahlung spectrum data for thick Al, Ti, Zr, Mo, and W targets by keV electron impact.

The data presented in this paper are related to the research paper entitled "Bremsstrahlung spectra produced by kilovolt electron impact on thick targets" [1]. The dataset includes our measured bremsstrahlung spectra on Al, Ti, Zr, Mo, and W thick targets at 5, 10, 15, 20, and 25 keV electron impact. In this paper we present the experimental method and make the dataset publicly available to enable extended analyses or reuse. The dataset is available on mendeley data public repository at http://dx.doi.org/10.17632/5zx3459bj3.1.

miRNA-223-3p regulates NLRP3 to promote apoptosis and inhibit proliferation of hep3B cells.

Hepatocellular carcinoma (HCC) is a major malignant tumor type with a high incidence and mortality. Infection with hepatitis virus is a high-risk factor. Previous studies have demonstrated that microRNA (miR)-223 was downregulated in HCC tissues. NOD-like receptor family, pyrin domain containing 3 (NLRP3)-is a potential target of miR-223 and has a vital role in hepatitis infection. The present study was performed to investigate the role of miR-223 in the proliferation and apoptosis of HCC cells through regulating NLRP3. A dual luciferase reporter assay was performed to confirm the direct interaction between miR-223-3p and the 3' untranslated region of NLRP3 mRNA. Hep3B cells were then transfected with miR-223 mimics and the proliferation and apoptosis were determined by an MTT and a flow cytometric assay, respectively. The expression of NLRP3 and caspase-1 was analyzed at the mRNA as well as at the protein level by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The secretion of interleukin (IL)-1ß and IL-18 in the culture supernatants was measured by ELISA. The dual luciferase assay confirmed NLRP3 as a direct target of miR-223. Overexpression of miR-223 in hep3B cells significantly suppressed cell proliferation and promoted apoptosis. Furthermore, the expression of NLRP3 was downregulated by miR-223 transfection. Certain downstream factors of the NLRP3 pathway were also downregulated following overexpression of miR-223. Caspase-1 was decreased at the transcriptional level and the cleaved caspase-1 was decreased at the protein level. Secretion of IL-1ß and IL-18 into the culture medium by cells transfected with miR-223 was lower than that by the control cells. In conclusion, the tumor suppressor role of miR-223 was associated with the regulation of NLRP3 inflammasome components. miR-223 inhibited HCC cell proliferation and promoted apoptosis by directly targeting NLRP3. Downstream production of caspase-1, IL-1ß and IL-18 were also repressed by miR-223. These results provided insight into the association between the innate immune system and the genesis of HCC.