Genomic hallmarks and therapeutic targets of ribosome biogenesis in cancer.

Hyperactive ribosome biogenesis (RiboSis) fuels unrestricted cell proliferation, whereas genomic hallmarks and therapeutic targets of RiboSis in cancers remain elusive, and efficient approaches to quantify RiboSis activity are still limited. Here, we have established an in silico approach to conveniently score RiboSis activity based on individual transcriptome data. By employing this novel approach and RNA-seq data of 14 645 samples from TCGA/GTEx dataset and 917 294 single-cell expression profiles across 13 cancer types, we observed the elevated activity of RiboSis in malignant cells of various human cancers, and high risk of severe outcomes in patients with high RiboSis activity. Our mining of pan-cancer multi-omics data characterized numerous molecular alterations of RiboSis, and unveiled the predominant somatic alteration in RiboSis genes was copy number variation. A total of 128 RiboSis genes, including EXOSC4, BOP1, RPLP0P6 and UTP23, were identified as potential therapeutic targets. Interestingly, we observed that the activity of RiboSis was associated with TP53 mutations, and hyperactive RiboSis was associated with poor outcomes in lung cancer patients without TP53 mutations, highlighting the importance of considering TP53 mutations during therapy by impairing RiboSis. Moreover, we predicted 23 compounds, including methotrexate and CX-5461, associated with the expression signature of RiboSis genes. The current study generates a comprehensive blueprint of molecular alterations in RiboSis genes across cancers, which provides a valuable resource for RiboSis-based anti-tumor therapy.

Magnetic Resonance Imaging to Assess Body Composition Change in Adolescents With Obesity After Sleeve Gastrectomy.

OBJECTIVES: Metabolic and bariatric surgery is the most effective weight loss treatment for severe obesity. The number of adolescents undergoing sleeve gastrectomy is increasing. We investigated changes in body composition in adolescents undergoing sleeve gastrectomy 12-26 weeks post-operatively using whole-body magnetic resonance imaging (WB-MRI). METHODS: This prospective cohort study assessed changes in adipose tissue compartments (ie, visceral, subcutaneous, and intermuscular) and muscle in 18 obese adolescents, ages 14-19, 89% female, with body mass index z -score of 2.6 ± 0.25 (range 2.16-3.2). All underwent WB-MRI 1.5-17 weeks pre-operatively and 12-26 weeks post-operatively. RESULTS: Pre- and post-operative WB-MRI showed decreases in all adipose tissue compartments, as well as decreased skeletal muscle and liver fat fraction ( P < 0.0001). The post-operative percentage loss of adipose tissue in subcutaneous, visceral, and intermuscular compartments (89.0%, 5.8%, 5.2%, respectively) was similar to the pre-operative percentages of corresponding adipose tissue compartments (90.5%, 5.0%, 4.5%, respectively). Of note, participants with obstructive sleep apnea had significantly higher pre-operative volume of subcutaneous and intermuscular adipose tissue than participants without obstructive sleep apnea ( P = 0.003). CONCLUSIONS: We found, contrary to what is reported to occur in adults, that pre-operative percentage loss of adipose tissue in subcutaneous, visceral, and intermuscular compartments was similar to the post-operative percentage loss of corresponding adipose tissue compartments in adolescents 12-26 weeks after sleeve gastrectomy.

APOBEC3 selects V179I in HIV-1 reverse transcriptase to provide selective advantage for non-nucleoside reverse transcriptase inhibitor-resistant mutants.

The V179I substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is selected in humans or mouse models treated with certain nonnucleoside reverse transcriptase inhibitors (NNRTIs). While it is often observed together with other NNRTI resistance mutations, V179I does not confer drug resistance. To understand how V179I arises during NNRTI treatment, we characterized it in HIV-1 molecular clones with or without the NNRTI resistance mutations Y181C or Y181V. While V179I alone did not confer resistance to any NNRTIs tested, when present with Y181C/V it enhanced drug resistance to some NNRTIs by 3- to 8-fold. In replication competition experiments in the presence of the NNRTI rilpivirine (RPV), V179I modestly enhanced Y181C HIV-1 or Y181V HIV-1 replication compared to viruses without V179I. As V179I arises from a G to A mutation, we evaluated whether it could arise due to host APOBEC3 deaminase activity and be maintained in the presence of a NNRTI to provide a selective advantage for the virus. V179I was detected in some humanized mice treated with RPV and was associated with G to A mutations characteristic of APOBEC3 activity. In RPV selection experiments, the frequency of V179I in HIV-1 was accelerated in CD4+ T cells expressing higher APOBEC3F and APOBEC3G levels. Our results provide evidence that V179I in HIV-1 RT can arise due to APOBEC-mediated G to A hypermutation and can confer a selective advantage to drug-resistant HIV-1 isolates in the presence of some NNRTIs.

Neuregulin1 acts as a suppressor in human lung adenocarcinoma via AKT and ERK1/2 pathway.

BACKGROUND: Neuregulin1 (NRG1) is critical signaling protein that mediates the activation of downstream signaling pathways associated with malignancies. Multiple gene fusions related to NRG1 have been found in lung cancer. However, the underlying role NRG1 in lung cancer is yet unclear. Therefore, the present study investigated the biological functions on human lung adenocarcinoma (LUAD). METHODS: The expression of NRG1 was detected in LUAD tissues by Western blot (WB), quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The expression of NRG1 was upregulated by the addition of exogenous NRG1 and downregulated by small interfering RNA (siRNA), and the biological behaviors of LUAD cells were assessed: cell proliferation by MTT assay, cell cycle and apoptosis by flow cytometry analysis, and migration and invasion using Transwell system. Finally, the pathway underlying the cellular function was analyzed by WB. RESULTS: A lower expression of NRG1 was observed in LUAD cancer tissues (P<0.05). Moreover, the addition of exogenous NRG1 reduced the cell proliferation, migration, and invasion (P<0.001), while the downregulation of endogenous NRG1 promoted the three kinds of biological behaviors of LUAD cell lines (P<0.001); however, these manifestations did no effect on the distribution of cell cycle and apoptosis status (P>0.05). Furthermore, the deficiency of NRG1 reduced the expression of p-ERK1/2 and p-AKT at the protein level (P<0.001). CONCLUSIONS: The current results suggested that NRG1 might be a suppressor in the development of LUAD, and its function was related to AKT and ERK1/2 pathway.

HP1α mediates defective heterochromatin repair and accelerates senescence in Zmpste24-deficient cells.

Heterochromatin protein 1 (HP1) interacts with various proteins, including lamins, to play versatile functions within nuclei, such as chromatin remodeling and DNA repair. Accumulation of prelamin A leads to misshapen nuclei, heterochromatin disorganization, genomic instability, and premature aging in Zmpste24-null mice. Here, we investigated the effects of prelamin A on HP1α homeostasis, subcellular distribution, phosphorylation, and their contribution to accelerated senescence in mouse embryonic fibroblasts (MEFs) derived from Zmpste24(-/-) mice. The results showed that the level of HP1α was significantly increased in Zmpste24(-/-) cells. Although prelamin A interacted with HP1α in a manner similar to lamin A, HP1α associated with the nuclease-resistant nuclear matrix fraction was remarkably increased in Zmpste24(-/-) MEFs compared with that in wild-type littermate controls. In wild-type cells, HP1α was phosphorylated at Thr50, and the phosphorylation was maximized around 30 min, gradually dispersed 2 h after DNA damage induced by camptothecin. However, the peak of HP1α phosphorylation was significantly compromised and appeared until 2 h, which is correlated with the delayed maximal formation of γ-H2AX foci in Zmpste24(-/-) MEFs. Furthermore, knocking down HP1α by siRNA alleviated the delayed DNA damage response and accelerated senescence in Zmpste24(-/-) MEFs, evidenced by the rescue of the delayed γ-H2AX foci formation, downregulation of p16, and reduction of senescence-associated ß-galactosidase activity. Taken together, these findings establish a functional link between prelamin A, HP1α, chromatin remodeling, DNA repair, and early senescence in Zmpste24-deficient mice, suggesting a potential therapeutic strategy for laminopathy-based premature aging via the intervention of HP1α.