INPP4B promotes colorectal cancer cell proliferation by activating mTORC1 signaling and cap-dependent translation.

BACKGROUND AND OBJECTIVE: Inositol polyphosphate 4-phosphatase type II (INPP4B) is over-expressed in CRC tissues, and emerges as an oncogene. However, the mechanism by which INPP4B regulates CRC cell proliferation remains largely unclear. In this study, we aimed to investigate the regulatory mechanisms of INPP4B in CRC. MATERIALS AND METHODS: The expression levels of mRNA were detected by qRT-PCR. The expression levels of protein were determined by Western blot. Cell Counting Kit-8 (CCK-8) assays and BrdU incorporation assays were performed to evaluate cell proliferation abilities. Bicistronic luciferase assays and the m7GTP pull down assay were performed to measure the cap-dependent translation in cells. RESULTS: INPP4B promotes CRC cell proliferation by increasing mTORC1 activity. Furthermore, it was shown that the activation of mTORC1 signaling by INPP4B led to increased cap-dependent translation, which is essential for INPP4B-mediated CRC cell proliferation. Finally, it was demonstrated that increased AKT and serum and glucocorticoid-inducible kinase 1 activity contributed to the activation of cap-dependent translation induced by INPP4B. CONCLUSION: Collectively, the present study reveals INPP4B promotes colorectal cancer cell proliferation by activating mTORC1 signaling and cap-dependent translation.

Maternal High Triglyceride Levels During Early Pregnancy and Risk of Preterm Delivery: A Retrospective Cohort Study.

CONTEXT: Maternal obesity increases the risk of preterm delivery. Obesity is known to be associated with altered lipid metabolism. OBJECTIVE: To investigate the associations between high maternal triglyceride (mTG) levels during early pregnancy and risks of preterm delivery stratified by early pregnancy body mass index (BMI). DESIGN: Retrospective cohort study. SETTING: University-based maternity center. PATIENTS: 49,612 women with singleton pregnancy who underwent fasting serum lipid screening during early pregnancy. MAIN OUTCOME MEASURES: Risk of preterm delivery (total, <37 weeks; early, 28 to 33 weeks; and late, 34 to 36 weeks). RESULTS: Among women enrolled, 2494 had a preterm delivery, including 438 early preterm and 2056 late preterm delivery. High mTG (>90th percentile, 2.04 mM) was associated with shortened gestation. Risks of total, early, and late preterm deliveries increased with mTG levels, and the high mTG-related risk was highest for early preterm delivery [adjusted odds ratio (AOR) 1.72; 95% CI, 1.30 to 2.29]. After stratification by BMI, high mTG was associated with risk of preterm delivery in both overweight or obese (OWO) women (AOR 1.32; 95% CI, 1.02 to 1.70) and women with normal BMI (AOR 1.36; 95% CI, 1.16 to 1.59). In additional sensitivity analyses, we found that high mTG was related to higher risks of preterm delivery among OWO women and women with normal BMI (AOR, 1.54; 95% CI, 1.07 to 2.22 and 1.62, 1.34 to 1.96, respectively), especially early preterm delivery (AOR 2.47; 95% CI, 1.19 to 5.10, and AOR 2.50; 95% CI, 1.65 to 3.78, respectively). CONCLUSIONS: High mTG level during early pregnancy increased the risks of preterm delivery not only in OWO women but also in women with normal BMI.

Integrated Transcriptome Sequencing Analysis Reveals Role of miR-138-5p/ TBL1X in Placenta from Gestational Diabetes Mellitus.

BACKGROUND/AIMS: The placenta has been suggested to play a crucial role in the pathology of gestational diabetes mellitus (GDM). Placenta-specific microRNAs (miRNAs) and the corresponding targeting genes involved in the pathology of GDM still remain to be elucidated. We aimed to identify the dysregulated miRNAs and the corresponding mRNA targets through an integrated miRNA and mRNA transcriptomic profiles analysis and investigate the role of differentially expressed miR-138-5p/TBL1X in GDM. METHODS: RNA sequencing (RNA-seq) was performed in 16 placentas from GDM and control group. Differentially expressed mRNAs and miRNAs in GDM were validated by quantitative PCR (qPCR). The wound healing assay and transwell migration assay were used to analyze cell migration ability. The cell proliferation was determined by CCK8 assay. Luciferase assay was used to confirm the direct binding of the targeted TBL1X with miR-138-5p. RESULTS: Totally, 281 mRNAs and 32 miRNAs were found to be differentially expressed in the GDM placentas. The biological relationships of the miRNA/mRNA pairs were related to cellular development and function and organ morphology. Among the aberrantly expressed molecules, we selected miR-138-5p from the bioinformatics analysis and found that miR-138-5p significantly inhibited the migration and proliferation of trophoblasts (HTR-8/SVneo) by targeting the 3'-UTR of TBL1X. Furthermore, the aberrant expression of miR-138-5p and TBL1X was significantly correlated with the weight of the placenta. CONCLUSION: We present the first integrative analysis of miRNA and mRNA expression profiles in GDM placenta and uncover a more detailed role for miR-138-5p, as well as its target TBL1X in the pathology of GDM.