MILIP Binding to tRNAs Promotes Protein Synthesis to Drive Triple-Negative Breast Cancer.

Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment. SIGNIFICANCE: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.

The N-Myc-responsive lncRNA MILIP promotes DNA double-strand break repair through non-homologous end joining.

The protooncoprotein N-Myc, which is overexpressed in approximately 25% of neuroblastomas as the consequence of MYCN gene amplification, has long been postulated to regulate DNA double-strand break (DSB) repair in neuroblastoma cells, but experimental evidence of this function is presently scant. Here, we show that N-Myc transcriptionally activates the long noncoding RNA MILIP to promote nonhomologous end-joining (NHEJ) DNA repair through facilitating Ku70-Ku80 heterodimerization in neuroblastoma cells. High MILIP expression was associated with poor outcome and appeared as an independent prognostic factor in neuroblastoma patients. Knockdown of MILIP reduced neuroblastoma cell viability through the induction of apoptosis and inhibition of proliferation, retarded neuroblastoma xenograft growth, and sensitized neuroblastoma cells to DNA-damaging therapeutics. The effect of MILIP knockdown was associated with the accumulation of DNA DSBs in neuroblastoma cells largely due to decreased activity of the NHEJ DNA repair pathway. Mechanistical investigations revealed that binding of MILIP to Ku70 and Ku80 increased their heterodimerization, and this was required for MILIP-mediated promotion of NHEJ DNA repair. Disrupting the interaction between MILIP and Ku70 or Ku80 increased DNA DSBs and reduced cell viability with therapeutic potential revealed where targeting MILIP using Gapmers cooperated with the DNA-damaging drug cisplatin to inhibit neuroblastoma growth in vivo. Collectively, our findings identify MILIP as an N-Myc downstream effector critical for activation of the NHEJ DNA repair pathway in neuroblastoma cells, with practical implications of MILIP targeting, alone and in combination with DNA-damaging therapeutics, for neuroblastoma treatment.

The alterations of gut microbiota in mice with chronic pancreatitis.

BACKGROUND: The changes of intestinal microbiome are associated with inflammatory, metabolic, and malignant disorders, and there are no studies assessing the intestinal microbiota of mice with chronic pancreatitis (CP). Thus, we aim to investigate the variations in diversity, composition and function of intestinal microbiota in CP mice. METHODS: Sixteen male C57BL/6 mice were randomly selected, and divided into two groups, treated intraperitoneally with saline (normal control group, CT group) or ethanol + cerulein (experimental group, CP group) for 6 weeks. Body weight as measured in entire processes. Histopathological examination of CP index was conducted to verify the CP induction. Extracted DNA from colon samples was used for Illumina HiSeq sequencing of the bacterial V4 region of 16S rRNA gene and analyzed using Quantitative Insights Into Microbial Ecology (QIIME). Functional profiling of microbial communities was predicted with BugBase. RESULTS: Significant alterations of the gut microbiota were found in the CP mice compared to CT groups, as revealed by significant decrease in bacterial richness and diversity, declined the relative abundance of Lachnospiraceae_NK4A136, Ruminiclostridium and Roseburia, and increased the relative abundances of Bacteroides and Alloprevotella genera. Analysis of microbial community-level phenotypes revealed significant differences in nine phenotypes (aerobic, anaerobic, containing mobile elements, facultatively anaerobic, biofilm forming, gram-negative, gram-positive, potentially pathogenic, and stress tolerant) between CP group and CT group. CONCLUSIONS: This study indicated that mice with CP had a distinct microbiota profile.

Vitamin B6 Intake and Pancreatic Carcinoma Risk: A Meta-Analysis.

Objectives: There are conflicting results for the association between vitamin B6 intake with reduced pancreatic carcinoma risk. Thus, a meta-analysis was performed to summarize the evidences from epidemiological studies. Methods: We searched documents from PubMed-Medline, Web of Science, and Cochrane Library. The results were analyzed by using Stata software. Results: A total of nine studies were included. The multivariate-adjusted results found that the total RR values of pancreatic carcinoma was 0.65 (95% CI: 0.53-0.80) for the highest vitamin B6 intake vs the lowest vitamin B6 intake, and there was no significant heterogeneity among studies (I2 = 42.0%, P = 0.087). Sensitivity analysis indicated that no single study leaded to an excessive change for the relation between vitamin B6 intake and pancreatic carcinoma risk. Conclusions: This meta-analysis suggested that vitamin B6 intake could significantly decrease pancreatic carcinoma risk. However, further study is needed based on the limitations of the current analysis.

Serum carbohydrate antigen 153 and renal function in patients with type 2 diabetes mellitus.

OBJECTIVE: The aim of our study was to investigate the correlation between serum carbohydrate antigen 153 (CA153) and renal function in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 184 patients with T2DM were included, and renal function was assessed by the modification of diet in renal disease (MDRD) formula adjusted coefficient of the Chinese people. RESULTS: Serum CA153 concentrations were positively correlated with blood glucose (BG) and glycated hemoglobin (HbA1c) (r = .204, P = .005; r = .165, P = .025) in patients with T2DM. There was a negative correlation between serum CA153 and estimated glomerular filtration rate (GFR) (r = -.229, P = .002) in whole patients with T2DM; similarly, the correlations were observed in both women and men (r = -.228, P = .028 for women, r = -.231, P = .028 for men). Multiple linear regression analysis suggested that serum CA153 was still significantly correlated with estimated GFR (beta = -0.286, P < .001). CONCLUSIONS: Serum CA153 is negatively correlated with estimated GFR in patients with T2DM, and serum CA153 may be a potentially useful clinical biomarker to assess renal function in the study population.