Melatonin suppresses tumor proliferation and metastasis by targeting GATA2 in endometrial cancer.

Endometrial cancer (EC) is a reproductive system disease that occurs in perimenopausal and postmenopausal women. However, its etiology is unclear. Melatonin (MT) has been identified as a therapeutic agent for EC; however, its exact mechanism remains unclear. In the present study, we determined that GATA-binding protein 2 (GATA2) is expressed at low levels in EC and regulated by MT. MT upregulates the expression of GATA2 through MT receptor 1A (MTNR1A), whereas GATA2 can promote the expression of MTNR1A by binding to its promoter region. In addition, in vivo and in vitro experiments showed that MT inhibited the proliferation and metastasis of EC cells by upregulating GATA2 expression. The protein kinase B (AKT) pathway was also affected. In conclusion, these findings suggest that MT and GATA2 play significant roles in EC development.

OPN N-glycosylation promoted bone destruction.

OBJECTIVES: Exploring the role of OPN N-glycosylation in osteoblasts and osteoclasts. METHODS: Immunohistochemistry was used to detect the expression of OPN in mice with apical periodontitis. The asparagine at position 79 of the OPN protein was mutated to glutamine, and the above plasmids were transfected into osteoblasts and osteoclasts. The effect of OPN N-glycosylation on proliferation of osteoblasts and osteoclasts was detected by CCK8 assays. Western blotting was used to detect the expression of OPN N-glycosylation on osteoclasts and osteoblasts. Detection of N-glycosylation of OPN activated the NF-κB signaling pathway to regulate osteoblasts and osteoclasts. RESULTS: OPN increased the expression in a mice model of apical periodontitis. The expression curve of OPN resembled a reverse V shape. The OPN N-glycosylation site was identified as 79 by MS. N-glycosylation of OPN promoted the proliferation of osteoclasts. But the N79 glycosylation site of mutant OPN could not increase the proliferation of osteoblasts. OPN N-glycosylation modulated the expression of osteoclast- and osteoblast-associated factors through the NF-κB signaling pathway. N-glycosylation of OPN promoted nuclear translocation of NF-κB in osteoclasts and osteoblasts. CONCLUSIONS: The N-glycosylation site of OPN is 79. N-glycosylation of OPN played an important role in the biological function of OPN protein.

miR-30a targets STOX2 to increase cell proliferation and metastasis in hydatidiform moles via ERK, AKT, and P38 signaling pathways.

BACKGROUND: A hydatidiform mole is a condition caused by abnormal proliferation of trophoblastic cells. MicroRNA miR-30a acts as a tumor suppressor gene in most tumors and participates in the development of various cancers. However, its role in hydatidiform moles is not clear. METHODS: Quantitative real-time reverse transcription PCR was used to verify the expression level of miR-30a and STOX2 (encoding storkhead box 2). Flow cytometry assays were performed to detect the cell cycle in cell with different expression levels of miR-30a and STOX2. Cell Cycle Kit-8, 5-ethynyl-2'-deoxyuridine, and colony formation assays were used to detect cell proliferation and viability. Transwell assays was used to test cell invasion and migration. Dual-luciferase reporter assays and western blotting were used to investigate the potential mechanisms involved. RESULT: Low miR-30a expression promoted the proliferation, migration, and invasion of trophoblastic cells (JAR and HTR-8). Dual luciferase assays confirmed that STOX2 is a target of miR-30a and resisted the effect of upregulated miR-30a in trophoblastic cells. In addition, downregulation of STOX2 by miR-30a could activate ERK, AKT, and P38 signaling pathways. These results revealed a new mechanism by which ERK, AKT, and P38 activation by miR-30a/STOX2 results in excessive proliferation of trophoblast cells in the hydatidiform mole. CONCLUSIONS: In this study, we found that miR-30a plays an important role in the development of the hydatidiform mole. Our findings indicate that miR-30a might promote the malignant transformation of human trophoblastic cells by regulating STOX2, which strengthens our understanding of the role of miR-30a in regulating trophoblastic cell transformation.

Paired-like homeodomain transcription factor 2 affects endometrial cell function and embryo implantation through the Wnt/ß-catenin pathway.

The successful implantation of embryos is crucial for pregnancy in mammals. This complex process is inevitably dependent on the development of the endometrium. The paired-like homeodomain transcription factor 2 (PITX2) is involved in a variety of biological processes, but whether it is involved in embryo implantation has not been reported. In this study, we aimed to investigate uterine expression and regulation of PITX2 during implantation. We found that PITX2 was elevated in the human endometrium in the secretory phase. The results of the pregnant mouse models showed that PITX2 expression was spatiotemporal in mouse endometrial tissue throughout peri-implantation period, and it was significantly upregulated at the time of implantation. Interestingly, PITX2 was mainly localized to the glandular epithelium cells on D2.5-3.5 of pregnancy, while D5.5-6.5 was largely expressed in stromal cells. In vitro, PITX2 regulated endometrial cells proliferation, migration, invasion, and other functions through the Wnt/ß-catenin signaling pathway. In addition, a significant decrease in the rate of embryo implantation was observed after injecting PITX2 small interfering RNA into the uterine horn. These results demonstrate the effects of PITX2 on the physiological function of endometrial cells and embryo implantation, suggesting a role in the endometrial regulatory mechanism during implantation.

MiR-30a-5p inhibits proliferation and metastasis of hydatidiform mole by regulating B3GNT5 through ERK/AKT pathways.

Hydatidiform moles are gestational trophoblastic disease. They are abnormal proliferations of trophoblast cells that have the potential to become cancerous. miR-miR30a-5p is a tumour suppressor that participates in the development of numerous diseases. However, the role of miR-30a in hydatidiform moles and the mechanisms underlying its effects are presently unclear. This study explored the levels of miR-30a and B3GNT5 expression in human hydatidiform mole tissue. The results showed that miR-30a and B3GNT5 were differentially expressed in normal placenta and hydatidiform mole, and miR-30a decreased cell proliferation, invasion and migration in trophoblast cell lines. Upon further examination, it was confirmed that miR-30a directly targeted the 3'untranslated region of B3GNT5 using a dual-luciferase assay. The results of the present study also revealed that miR-30a reduced the proliferation, invasion and migration ability in JAR and BeWo cells by regulating B3GNT5, which may inactivate the ERK and AKT signalling pathways. This study demonstrated that miR-30a was a novel target B3GNT5 that serves an important role in the development of hydatidiform moles, suggesting that miR-30a may serve as a novel potential biomarker or useful diagnostic and therapeutic tool for hydatidiform moles in clinical settings.

Fucoxanthin inhibits tumour-related lymphangiogenesis and growth of breast cancer.

Tumour lymphangiogenesis plays an important role in promoting the growth and lymphatic metastasis of tumours. The process is associated with cell proliferation, migration and tube-like structure formation in lymphatic endothelial cells (LEC), but no antilymphangiogenic agent is currently used in clinical practice. Fucoxanthin is a material found in brown algae that holds promise in the context of drug development. Fucoxanthin is a carotenoid with variety of pharmacological functions, including antitumour and anti-inflammatory effects. The ability of fucoxanthin to inhibit lymphangiogenesis remains unclear. The results of experiments performed as part of this study show that fucoxanthin, extracted from Undaria pinnatifida (Wakame), inhibits proliferation, migration and formation of tube-like structures in human LEC (HLEC). In this study, fucoxanthin also suppressed the malignant phenotype in human breast cancer MDA-MB-231 cells and decreased tumour-induced lymphangiogenesis when used in combination with a conditional medium culture system. Fucoxanthin significantly decreased levels of vascular endothelial growth factor (VEGF)-C, VEGF receptor-3, nuclear factor kappa B, phospho-Akt and phospho-PI3K in HLEC. Fucoxanthin also decreased micro-lymphatic vascular density (micro-LVD) in a MDA-MB-231 nude mouse model of breast cancer. These findings suggest that fucoxanthin inhibits tumour-induced lymphangiogenesis in vitro and in vivo, highlighting its potential use as an antilymphangiogenic agent for antitumour metastatic comprehensive therapy in patients with breast cancer.

The potential role of Annexin 3 in diapause embryo restart of Artemia sinica and in response to stress of low temperature.

Annexins are highly conserved and ubiquitous in various somatic cell types. They are involved in membrane transport and a range of calcium-regulated activities on the cell membrane surface, including vesicular transport, membrane fusion in exocytosis, signal transduction, and formation of calcium channels. They also regulate inflammatory response, cell differentiation, and interaction between cytoskeletal proteins. In this study, for the first time, an ANX3 gene from Artemia sinica ( As-anx3) was cloned. The As-anx3 full-length complementary DNA comprises 1,024 bp and has a 948 bp open reading frame encoding a 315-amino-acid polypeptide with four ANX domains. The profiles of both As-ANX3 mRNA and protein expression exhibited peaks at the 0 hr stage and had the same significant downregulation trend throughout the post-diapause embryo development stage. The ERK1/2, the phosphorylation levels of ERK1/2, and cell cycle-related protein (CDK4) expressions were analyzed by western blot analysis. The results showed that CDK4 presented a significantly ascending trend from 0 and 40 hr, although the phosphorylation levels of ERK1/2 did not increase significantly. The transcriptional and protein expressions of As-ANX3 were highly upregulated when the temperature was lowered from 25 to 15°C, but the expressions showed a gradual downward trend when the temperature was further lowered to 5°C. These results indicated that As-ANX3 plays a crucial role in restarting diapause and low-temperature stress in A. sinica.

Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization.

Dynamic epigenetic reprogramming occurs during normal embryonic development at the preimplantation stage. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF) are linked to various short- or long-term consequences. Among these, the skewed sex ratio, an indicator of reproductive hazards, was reported in bovine and porcine embryos and even human IVF newborns. However, since the first case of sex skewing reported in 1991, the underlying mechanisms remain unclear. We reported herein that sex ratio is skewed in mouse IVF offspring, and this was a result of female-biased peri-implantation developmental defects that were originated from impaired imprinted X chromosome inactivation (iXCI) through reduced ring finger protein 12 (Rnf12)/X-inactive specific transcript (Xist) expression. Compensation of impaired iXCI by overexpression of Rnf12 to up-regulate Xist significantly rescued female-biased developmental defects and corrected sex ratio in IVF offspring. Moreover, supplementation of an epigenetic modulator retinoic acid in embryo culture medium up-regulated Rnf12/Xist expression, improved iXCI, and successfully redeemed the skewed sex ratio to nearly 50% in mouse IVF offspring. Thus, our data show that iXCI is one of the major epigenetic barriers for the developmental competence of female embryos during preimplantation stage, and targeting erroneous epigenetic modifications may provide a potential approach for preventing IVF-associated complications.

Osteopontin Promotes Bone Destruction in Periapical Periodontitis by Activating the NF-κB Pathway.

BACKGROUND/AIMS: Periapical periodontitis is caused by bacterial infection and results in both one destruction and tooth loss. Osteopontin (OPN) is a secreted phosphorylated glycoprotein that participates in bone metabolism. METHODS: Thirty-three patients with chronic periapical periodontitis and 10 patients who had undergone the orthodontic removal of healthy tooth tissue (control) at the periodontal ligament were investigated, and an animal model of mouse periapical periodontitis was established for an in vivo analysis. The relationship between OPN and bone destruction during periapical periodontitis was analyzed. Osteoblasts and osteoclasts were cultured in vitro and treated with lipopolysaccharide. An inhibitor of NF-κB was used to pretreat the transfected cells. RESULTS: OPN increased osteoclast proliferation and differentiation, but reduced osteoblasts proliferation and differentiation. OPN activated the NF-κB pathway during periapical periodontitis and accelerated the transfer and phosphorylation of P65 from the cytoplasm to the nucleus. CONCLUSION: This study demonstrated that OPN played important roles in the progression of periapical periodontitis, and a dual role in bone metabolism during periapical periodontitis, linking osteoclasts and osteoblasts. The underlying mechanism may be related to the NF-κB pathway.

Aquaporin-3 mediates ovarian steroid hormone-induced motility of endometrial epithelial cells.

STUDY QUESTION: How does aquaporin-3 (AQP3) affect endometrial receptivity? SUMMARY ANSWER: AQP3, which is regulated by the combination and estrogen (E2) and progesterone (P4), induces epithelial-mesenchymal transition (EMT) of endometrial epithelial cells. WHAT IS KNOWN ALREADY: Embryo implantation is an extremely complex process, and endometrial receptivity is essential for successful embryo implantation. Estrogen and progesterone regulate endometrial receptivity. AQP3, which is regulated by estrogen (E2), increases cell migration and invasion ability by regulating the expression of EMT-related factors and influencing the reorganization of the actin cytoskeleton. STUDY DESIGN, SIZE, DURATION: This study investigated the pathophysiological significance of AQP3 in human endometrial function during different phases of the menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: AQP3 expression levels during different phases of the menstrual cycle were measured using immunohistochemical assays. In cells of different receptivity (high-receptive RL95-2 cells and low-receptive HEC-1A cells), the expression of AQP3 was measured using western blotting, qRT-PCR and immunofluorescence assays. Activities of AQP3, and its regulation by E2 and P4, were studied through in-vitro experiments using RL95-2 cells. MAIN RESULTS AND THE ROLE OF CHANCE: AQP3 expression in the mid- and late-secretory phases of the human endometrium is significantly higher than in other phases. Since AQP3 expression levels were higher in RL95-2 cells than in HEC-1A cells, mechanisms of AQP3 regulation by E2 and P4 were studied using RL95-2 cells. We provided the first report that P4 up-regulates AQP3 by directly targeting the promoter of the AQP3 gene. The up-regulation of AQP3 expression by a combination of E2 and P4 is significantly higher than that caused by either E2 or P4 alone. Together E2 and P4 promote RL95-2 cell migration and invasion by inducing EMT through AQP3. We also found that AQP3 co-localizes with ezrin and affects the formation of filopodia and lamellipodia during the E2 and P4-induced EMT process but has no effect on the expression of ezrin and F-actin. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: It is still unclear whether AQP3 is a main regulator of endometrial receptivity or one of several factors influencing the process. WIDER IMPLICATIONS OF THE FINDINGS: Further investigation on AQP3 may contribute to a greater understanding of endometrial receptivity. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Scientific Grants of China (No. 31570798), the Program for Liaoning Excellent Talents in University (LR2017042), the Doctoral Scientific Research Foundation of Liaoning province (201601236), and the Liaoning Provincial Program for Top Discipline of Basic Medical Sciences. There are no conflicts of interest.

The Potential Roles of the Apoptosis-Related Protein PDRG1 in Diapause Embryo Restarting of Artemia sinica.

High salinity and low temperatures can induce Artemia sinica to enter the diapause stage during embryonic development. Diapause embryos stop at the gastrula stage, allowing them to resist apoptosis and regulate cell cycle activity to guarantee normal development after diapause termination. P53 and DNA damage-regulated gene 1 (pdrg1) is involved in cellular physiological activities, such as apoptosis, DNA damage repair, cell cycle regulation, and promotion of programmed cell death. However, the role of pdrg1 in diapause and diapause termination in A. sinica remains unknown. Here, the full-length A. sinica pdrg1 cDNA (As-pdrg1) was obtained and found to contain 1119 nucleotides, including a 228 bp open reading frame (ORF), a 233 bp 5'-untranslated region (UTR), and a 658-bp 3'-UTR, which encodes a 75 amino acid protein. In situ hybridization showed no tissue specific expression of As-pdrg1. Quantitative real-time PCR and western blotting analyses of As-pdrg1 gene and protein expression showed high levels at 15-20 h of embryo development and a subsequent downward trend. Low temperatures upregulated As-pdrg1 expression. RNA interference for the pdrg1 gene in Artemia embryos caused significant developmental hysteresis. Thus, PDRG1 plays an important role in diapause termination and cell cycle regulation in early embryonic development of A. sinica.

High-resolution profiles of gene expression and DNA methylation highlight mitochondrial modifications during early embryonic development.

Well-organized mitochondrial functions and dynamics are critical for early embryonic development and are operated via a large number of mitochondria-related genes (MtGs) encoded by both the nuclear and the mitochondrial genome. However, the mechanisms underlying mitochondrial modifications during the critical window between blastocyst implantation and postimplantation organogenesis are poorly understood. Herein, we performed high-resolution dynamic profiling of MtGs to acquire a more detailed understanding of mitochondrial modifications during early development. Our data suggest that the resumption of mitochondrial mass growth is not only facilitated by increased mitochondrial biogenesis and mitochondrial DNA (mtDNA) replication, but also by the appropriate balance between mitochondrial fission and fusion. In addition, increased levels of reactive oxygen species (ROS) resulting from enhanced mitochondrial functions may be the critical inducer for activating the glutathione (GSH)-based stress response system in early embryos. The appropriate balance between the mitochondrial stress response and apoptosis appears to be significant for cell differentiation and early organogenesis. Furthermore, we found that most MtGs undergo de novo promoter methylation, which may have functional consequences on mitochondrial functions and dynamics during early development. We also report that mtDNA methylation can be observed as early as soon after implantation. DNMT1, the predominant enzyme for maintaining DNA methylation, localized to the mitochondria and bound to mtDNA by the implantation stage. Our study provides a new insight into the involvement of mitochondria in early mammalian embryogenesis. We also propose that the epigenetic modifications during early development are significant for modulating mitochondrial functions and dynamics.

Dynamic integrated analysis of DNA methylation and gene expression profiles in in vivo and in vitro fertilized mouse post-implantation extraembryonic and placental tissues.

STUDY HYPOTHESIS: How does in vitro fertilization (IVF) alter promoter DNA methylation patterns and its subsequent effects on gene expression profiles during placentation in mice? STUDY FINDING: IVF-induced alterations in promoter DNA methylation might have functional consequences in a number of biological processes and functions during IVF placentation, including actin cytoskeleton organization, hematopoiesis, vasculogenesis, energy metabolism and nutrient transport. WHAT IS KNOWN ALREADY: During post-implantation embryonic development, both embryonic and extraembryonic tissues undergo de novo DNA methylation, thereby establishing a global DNA methylation pattern, and influencing gene expression profiles. Embryonic and placental tissues of IVF conceptuses can have aberrant morphology and functions, resulting in adverse pregnancy outcomes such as pregnancy loss, low birthweight, and long-term health effects. To date, the IVF-induced global profiling of DNA methylation alterations, and their functional consequences on aberrant gene expression profiles in IVF placentas have not been systematically studied. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Institute for Cancer Research mice (6 week-old females and 8-9 week-old males) were used to generate in vivo fertilization (IVO) and IVF blastocysts. After either IVO and development (IVO group as control) or in vitro fertilization and culture (IVF group), blastocysts were collected and transferred to pseudo-pregnant recipient mice. Extraembryonic (ectoplacental cone and extraembryonic ectoderm) and placental tissues from both groups were sampled at embryonic day (E) 7.5 (IVO, n = 822; IVF, n = 795) and E10.5 (IVO, n = 324; IVF, n = 278), respectively. The collected extraembryonic (E7.5) and placental tissues (E10.5) were then used for high-throughput RNA sequencing (RNA-seq) and methylated DNA immunoprecipitation sequencing (MeDIP-seq). The main dysfunctions indicated by bioinformatic analyses were further validated using molecular detection, and morphometric and phenotypic analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Dynamic functional profiling of high-throughput data, together with molecular detection, and morphometric and phenotypic analyses, showed that differentially expressed genes dysregulated by DNA methylation were functionally involved in: (i) actin cytoskeleton disorganization in IVF extraembryonic tissues, which may impair allantois or chorion formation, and chorioallantoic fusion; (ii) disturbed hematopoiesis and vasculogenesis, which may lead to abnormal placenta labyrinth formation and thereby impairing nutrition transport in IVF placentas; (iii) dysregulated energy and amino acid metabolism, which may cause placental dysfunctions, leading to delayed embryonic development or even lethality; (iv) disrupted genetic information processing, which can further influence gene transcriptional and translational processes. LIMITATIONS, REASONS FOR CAUTION: Findings in mouse placental tissues may not be fully representative of human placentas. Further studies are necessary to confirm these findings and determine their clinical significance. WIDER IMPLICATIONS OF THE FINDINGS: Our study is the first to provide the genome-wide analysis of gene expression dysregulation caused by DNA methylation during IVF placentation. Systematic understanding of the molecular mechanisms implicated in IVF placentation can be useful for the improvement of existing assisted conception systems to prevent these IVF-associated safety concerns. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by grants from the National Natural Science Foundation of China (No. 31472092), and the National High-Tech R&D Program (Nos. 2011|AA100303, 2013AA102506). There was no conflict of interest.

Osteopontin Promotes Invasion, Migration and Epithelial-Mesenchymal Transition of Human Endometrial Carcinoma Cell HEC-1A Through AKT and ERK1/2 Signaling.

BACKGROUND/AIMS: Osteopontin (OPN) is an Extracellular Matrix (ECM) molecule and is involved in many physiologic and pathologic processes, including cell adhesion, angiogenesis and tumor metastasis. OPN is a well-known multifunctional factor involved in various aspects of cancer progression, including endometrial cancer. In this study, we examined the significance of OPN in endometrial cancer. METHODS: The proliferation, migration and invasion ability of HEC-1A cells were detected by Cell Counting Kit-8 (CCK-8), Wound scratch assay and transwell. Western blots were employed to detect the expression of Matrix metalloproteinase-2 (MMP-2) and epithelial-mesenchymal transition (EMT)-related factors in HEC-1A cells treated with rhOPN. RESULTS: rhOPN promotes cell proliferation, migration and invasion in HEC-1A cells. rhOPN influenced EMT-related factors and MMP-2 expression in HEC-1A cells. rhOPN promoted HEC-1A cells migration, invasion and EMT through protein kinase B (PKB/AKT) and Extracellular regulated protein kinases (ERK1/2) signaling pathway. CONCLUSIONS: These results may open up a novel therapeutic strategy for endometrial cancer: namely, rhOPN have important roles in controlling growth of endometrial of cancer cells and suggest a novel target pathway for treatment of this cancer.

Induction of forkhead box M1 (FoxM1) by EGF through ERK signaling pathway promotes trophoblast cell invasion.

Successful placentation depends on the proper invasion of extravillous trophoblast (EVT) cells into maternal tissues. Previous reports have demonstrated that FoxM1 is oncogenic and plays important roles in angiogenesis, invasion, and metastasis. However, little is known about the roles of FoxM1 in the invasion of EVT cells. EGF, as a growth factor (epidermal growth factor), has been studied extensively in reproduction. JAR cells are a reliable model for studying early invasive trophoblast regulation. We have observed the relationship between EGF and FoxM1 in JAR cells by using specific inhibitors for the intervention in and study of potential signal pathways. We have also tested the ability of JAR cells to be influenced by the expression of FoxM1. Our data indicate that EGF promotes FoxM1 expression through the ERK signal pathway. Over-FoxM1 expression upregulates the ability of JAR cells to migrate and invade and vice versa. Our investigation of FoxM1 should provide new insights into the molecular mechanisms of EVT invasion.

Dynamic proteomic profiles of in vivo- and in vitro-produced mouse postimplantation extraembryonic tissues and placentas.

As the interface between the mother and the developing fetus, the placenta is believed to play an important role in assisted reproductive technology (ART)-induced aberrant intrauterine and postnatal development. However, the mechanisms underlying aberrant placentation remain unclear, especially during extraembryonic tissue development and early stages of placental formation. Using a mouse model, this investigation provides the first comparative proteomic analysis of in vivo (IVO) and in vitro-produced (IVP) extraembryonic tissues and placentas after IVO fertilization and development, or in vitro fertilization and culture, respectively. We identified 165 and 178 differentially expressed proteins (DEPs) between IVO and IVP extraembryonic tissues and placentas on Embryonic Day 7.5 (E7.5) and E10.5, respectively. Many DEPs were functionally associated with genetic information processing, such as impaired de novo DNA methylation, as well as posttranscriptional, translational and posttranslational dysregulation. These novel findings were further confirmed by global hypomethylation, and a lower level of correlation was found between the transcriptome and proteome in the IVP groups. In addition, numerous DEPs were involved in energy and amino acid metabolism, cytoskeleton organization and transport, and vasculogenesis and angiogenesis. These disturbed processes and pathways are likely to be associated with embryonic intrauterine growth restriction, an enlarged placenta, and impaired labyrinth morphogenesis. This study provides a direct and comprehensive reference for the further exploration of the placental mechanisms that underlie ART-induced developmental aberrations.

Comparative analysis of dynamic proteomic profiles between in vivo and in vitro produced mouse embryos during postimplantation period.

Assisted reproductive technology (ART) increasingly is associated with long-term side-effects on postnatal development and behaviors. High-throughput gene expression analysis has been extensively used to explore mechanisms responsible for these disorders. Our study, for the first time, provides a comparative proteomic analysis between embryos after in vivo fertilization and development (IVO, control) and in vitro fertilization and culture (IVP). By comparing the dynamic proteome during the postimplantation period, we identified 300 and 262 differentially expressed proteins (DEPs) between IVO and IVP embryos at embryonic day 7.5 (E7.5) and E10.5, respectively. Bioinformatic analysis showed many DEPs functionally associated with post-transcriptional, translational, and post-translational regulation, and these observations were consistent with correlation analysis between mRNA and protein abundance. In addition to altered gene expression due to IVP procedures, our findings suggest that aberrant processes at these various levels also contributed to proteomic alterations. In addition, numerous DEPs were involved in energy and amino acid metabolism, as well as neural and sensory development. These DEPs are potential candidates for further exploring the mechanism(s) of ART-induced intrauterine growth restriction and neurodevelopmental disorders. Moreover, significant enrichment of DEPs in pathways of neurodegenerative diseases implies the potentially increased susceptibility of ART offspring to these conditions as adults.

OPN up-regulated proliferation and invasion of head and neck squamous cell carcinoma through the p38MAPK signaling pathway.

OBJECTIVE: Osteopontin (OPN) is aberrantly expressed in various tumors. However, its role and detailed mechanisms in head and neck squamous cell carcinoma (HNSCC) have not been extensively described. STUDY DESIGN: Expression of OPN in HNSCC was examined at the gene and protein levels. The effect of cell proliferation ability was examined by Cell Counting Kit-8, colony formation assay, cell invasiveness by Transwell assay, the effect of OPN on protein expression of Capase-3 and Bcl2 by Western blotting, and the expression of p38MAPK signaling pathway by p38MAPK inhibitor SB203580. RESULTS: We found that OPN expression was higher in human HNSCC tissues than in adjacent tissues. Osteopontin may regulate the proliferation and invasion of HNSCC cells through the p38-MAPK signaling pathway. DISCUSSION: Our study identifies an important role for OPN in HNSCC and further demonstrates that it may regulate the proliferation and invasion of HNSCC cells by activating the p38-MAPK signaling pathway. Osteopontin may be a promising prognostic and diagnostic indicator and a potential target for cancer therapy.

Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy.

Hematological malignancies are one of the most lethal illnesses that seriously threaten human life and health. Lipids are important constituents of various biological membranes and substances for energy storage and cell signaling. Furthermore, lipids are critical in the normal physiological activities of cells. In the process of the lethal transformation of hematological malignancies, lipid metabolism reprogramming meets the material and energy requirements of rapidly proliferating and dividing tumor cells. A large number of studies have shown that dysregulated lipid metabolism, commonly occurs in hematological malignancies, mediating the proliferation, growth, migration, invasion, apoptosis, drug resistance and immune escape of tumor cells. Targeting the lipid metabolism pathway of hematological malignancies has become an effective therapeutic approach. This article reviews the oncogenic mechanisms of lipid metabolism reprogramming in hematological malignancies, including fatty acid, cholesterol and phospholipid metabolism, thereby offering an insight into targeting lipid metabolism in the treatment of hematological malignancies.