Time is of the essence: the molecular mechanisms of primary microcephaly

Primary microcephaly is a brain growth disorder characterized by a severe reduction of brain size and thinning of the cerebral cortex. Many primary microcephaly mutations occur in genes that encode centrosome proteins, highlighting an important role for centrosomes in cortical development. Centrosomes are microtubule organizing centers that participate in several processes, including controlling polarity, catalyzing spindle assembly in mitosis, and building primary cilia. Understanding which of these processes are altered and how these disruptions contribute to microcephaly pathogenesis is a central unresolved question. In this review, we revisit the different models that have been proposed to explain how centrosome dysfunction impairs cortical development. We review the evidence supporting a unified model in which centrosome defects reduce cell proliferation in the developing cortex by prolonging mitosis and activating a mitotic surveillance pathway. Finally, we also extend our discussion to centrosome-independent microcephaly mutations, such as those involved in DNA replication and repair.

Mechanism of long-chain non-coding RNA hypoxia-inducible factor 1α-antisense RNA 1 regulating chemotherapy resistance of retinoblastoma by inhibiting hypoxia-inducible factor-α expression

Retinoblastoma (Rb) mostly occurs in infants and young children with weak resistance. Surgical treatment causes great damage to children’s appearance, so adjuvant chemotherapy is needed to reduce the damage. But chemotherapeutic resistance affects treatment effectiveness and may even lead to the death of the child. Exploring the specific mechanism of drug resistance in Rb children is helpful to improve the therapeutic effect. It was found that the relative expression in Rb cell Y79, SO-Rb50, and HXO-Rb44 was greatly higher than that in normal hum an retinal cells. After transfection of SI-HIF1A-AS1 into Rb cells, the expression of lncRNA HIF1A-AS1 was decreased greatly, and the level of HIF-1α was down-regulated. Suppress lncRNA HIF1A-AS1 expression can reduce cell proliferation and improve apoptosis. Based on the overexpression of HIF-1α, the cell proliferation ability was restored partially, and the apoptosis ability was reduced greatly. When cells were cultured with vincristine, we found that suppress lncRNA HIF1A-AS1 expression can decrease cell survival, and overexpression of HIF-1α improved cell survival. The above results confirmed that inhibition of lncRNA HIF1AAS1 expression could reduce drug resistance of Y97 cells, while overexpression of HIF-1α can antagonize the drug resistance of low expression lncRNA HIF1A-AS1 against Rb cells. Therefore, this study suggests that lncRNA HIF1A-AS1 may regulate Rb cells’ resistance to vincristine by regulating HIF-1α expression.

The LINC00152/miR-138 Axis Facilitates Gastric Cancer Progression by Mediating SIRT2

Gastric cancer (GC) is the most common gastrointestinal cancer and the main cause of tumor-related death. Exploring markers for early diagnosis and new therapeutic targets is always on the way. In the last 10 years, long noncoding RNAs (lncRNAs) have been widely proved to be involved in the progress of many tumors and are regarded as potential targets for tumor therapy. We found that LINC00152, a newly identified lncRNA, was significantly upregulated in GC tissues and affected clinicopathological characteristics in GC patients. Furthermore, we observed that LINC00152 knockdown can significantly reduce cell proliferation and promote apoptosis in human gastric cancer cells. Further bioinformatic analysis indicated that LINC00152 competitively bound with miR-138 and regulated the expression of miR-138. Moreover, SIRT2 was further proved to be a downstream target of miR-138. Overall, this study elucidates the molecular mechanism of LINC00152 underlying the malignant phenotype of GC cells by mediating miR-138/SIRT2 axis, which provides a new understanding of the role and molecular mechanism of lncRNA in GC and also provides a new way for the treatment of gastric cancer.

Blocking Estrogen Synthesis Leads to Different Hormonal Responses in Canine and Human Triple Negative Inflammatory Breast Cancer

Blocking estrogen synthesis by inhibitors of estrogen synthesis is a widely used therapy against estrogen receptor-positive tumors. However, these therapies are less effective in negative expression tumors. Therefore, this study determined the effectiveness of anti-aromatase and anti-sulfatase therapies in canine and human inflammatory breast cancer. Cell cultures and xenografts from IPC-366 and SUM149 were treated with different doses of letrozole (anti-aromatase) and STX-64 (anti-sulfatase), in order to observe their effectiveness in terms of cell proliferation, tumor progression, and the appearance of metastases and hormonal profiles. The results revealed that both treatments are effective in vitro since they reduce cell proliferation and decrease the secreted estrogen levels. In xenograft mice, while treatment with letrozole reduces tumor progression by 30–40%, STX-64 increases tumor progression by 20%. The hormonal results obtained determined that STX-64 produced an increase in circulating and intratumoral levels of estradiol, which led to an increase in tumor progression. However, letrozole was able to block estrogen synthesis by decreasing the levels of circulating and intratumoral estrogen and thus slowing down tumor progression. In conclusion, letrozole can be an effective treatment for canine and human inflammatory breast cancer. The knowledge of the hormonal profile of breast tumors reflects useful information on the effectiveness of different endocrine treatments.

Differential effects of HIF2α antagonist and HIF2α silencing in renal cancer and sensitivity to repurposed drugs

Background In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. Methods We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385. Results PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity. Conclusions: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.

Orai1 Downregulation Causes Proliferation Reduction and Cell Cycle Arrest via Inactivation of the Ras-NF-κB Signaling Pathway in Osteoblasts

Background: The purpose of this study was to determine the role of Orai1 in the regulation of the proliferation and cell cycle of osteoblasts. Methods: The expression of Orai1 was inhibited by Orai1 small interfering RNA (siRNA) in MC3T3-E1 cells. Following Orai1 downregulation, cell proliferation and cell cycle were examined. Furthermore, the expression of cyclin D1, cyclin E, CDK4, and CDK6 was analyzed. The activity of the Ras-NF-κB signaling pathway was investigated to identify the role of Orai1 in the regulation of osteoblast proliferation. Results: Orai1 was successfully downregulated in MC3T3-E1 cells by the Orai1 siRNA transfection (p <0.05). We found that MC3T3-E1 cell proliferation was decreased, and the cell cycle was arrested by Orai1 downregulation (p <0.05). Additionally, the expression of cyclin D1 was decreased by Orai1 downregulation (p <0.05), as was the activity of the Ras-NF-κB signaling pathway (p <0.05). Orai1 siRNA did not further reduce cell proliferation, the proportion of cells in the S phase, and cyclin D1 expression after chemical blockage of the Ras signaling pathway in MC3T3-E1 cells (p >0.05).Conclusions: The results reveal that Orai1 downregulation may reduce cyclin D1 expression by inactivating the Ras-NF-κB signaling pathway thus blocking osteoblast proliferation and cell cycle.

LINC01089 suppresses lung adenocarcinoma cell proliferation and migration via miR-301b-3p/STARD13 axis

Background Lung adenocarcinoma (LUAD) is one of the most common cancers with high morbidity and mortality worldwide. Long non-coding RNAs (lncRNAs) serve as tumor promoters or suppressors in the development of various human malignancies, including LUAD. Although long intergenic non-protein coding RNA 1089 (LINC01089) suppresses the progression of breast cancer, its mechanism in LUAD requires further exploration. Thus, we aimed to investigate the underlying function and mechanism of LINC01089 in LUAD. Methods The expression of LINC01089 in LUAD and normal cell lines was detected. Functional assays were applied to measure cell proliferation, apoptosis and migration. Besides, mechanism experiments were employed for assessing the interplay among LINC01089, miR-301b-3p and StAR related lipid transfer domain containing 13 (STARD13). Data achieved in this study was statistically analyzed with Student’s t test or one-way analysis of variance. Results LINC01089 expression was significantly down-regulated in LUAD tissues and cells and its overexpression could reduce cell proliferation and migration. Moreover, LINC01089 could regulate STARD13 expression through competitively binding to miR-301b-3p in LUAD. Additionally, rescue assays uncovered that STARD13 depletion or miR-301b-3p overexpression could countervail the restraining effect of LINC01089 knockdown on the phenotypes of LUAD cells. Conclusion LINC01089 served as a tumor-inhibitor in LUAD by targeting miR-301b-3p/STARD13 axis, providing an innovative insight into LUAD therapies. Trial registration Not applicable.

Exploring molecular mechanism of novel liposomal nanoparticles application in glioma

This study investigated whether miR-509 plays a role in regulating autophagy and apoptosis-related caspase 3 genes, and analyzes targeted nanoparticles intervention in glioma cells. The surgically resected glioma tissue specimens were included as observation group, and control group used a 2-cm open tissue next to the glioma followed by analysis of miR-509 and caspase 3 level by qPCR. Glioma cell line U251 was divided into miRNC group, targeted nanoparticle group, siRNA-NC group, and siRNA-caspase 3 group, followed by analysis of caspase 3 expression, cell proliferation by flow cytometry, and cell invasion and metastasis by trans well. Caspase 3 mRNA expression was significantly higher in glioma tissues compared with controls. Lower miR-509 and higher caspase 3 expression were correlated with TNM stage. Caspase 3 mRNA level was significantly higher and miR-509 was lower in glioma cells or glioma ell line U251 than those in normal cells. Transfection of siRNA-caspase 3, targeted nanoparticles effectively reduced cell proliferation, metastasis, and invasion and down-regulated caspase 3 levels in U251 cells. Reduced miR-509 expression was associated with elevated caspase 3 expression and enhanced invasive metastatic capacity of glioma cells. Overexpression of miR-509 can effectively reduce cell proliferation, metastasis, and invasion by targeted nanoparticles inhibiting caspase 3 expression.

Orai1 Downregulation Causes Proliferation Reduction and Cell Cycle Arrest via Inactivation of the Ras-NF-κB Signaling Pathway in Osteoblasts

Objective: The purpose of this study was to determine the role of Orai1 in the regulation of the proliferation and cell cycle of osteoblasts. Methods: The expression of Orai1 was inhibited by Orai1 small interfering RNA (siRNA) in MC3T3-E1 cells. Following Orai1 downregulation, cell proliferation and cell cycle were examined. Furthermore, the expression of cyclin D1, cyclin E, CDK4, and CDK6 was analyzed. The activity of the Ras-NF-κB signaling pathway was investigated to identify the role of Orai1 in the regulation of osteoblast proliferation. Results: Orai1 was successfully downregulated in MC3T3-E1 cells by the Orai1 siRNA transfection (p <0.05). We found that MC3T3-E1 cell proliferation was decreased, and the cell cycle was arrested by Orai1 downregulation (p <0.05). Additionally, the expression of cyclin D1 was decreased by Orai1 downregulation (p <0.05), as was the activity of the Ras-NF-κB signaling pathway (p <0.05). Orai1 siRNA did not further reduce cell proliferation, the proportion of cells in the S phase, and cyclin D1 expression after chemical blockage of the Ras signaling pathway in MC3T3-E1 cells (p >0.05).Conclusion: The results reveal that Orai1 downregulation may reduce cyclin D1 expression by inactivating the Ras-NF-κB signaling pathway thus blocking osteoblast proliferation and cell cycle.

The role of statins in lung cancer

Lung cancer is one of the most common causes of cancer-related mortality in the 21st century. Statins as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase not only reduce the cholesterol levels in the blood and decrease the risk of cardiovascular disease but may also play an important role in the prevention and treatment of lung cancer. Statins have several antitumor properties including the ability to reduce cell proliferation and angiogenesis, decrease invasion and synergistic suppression of lung cancer progression. Statins induce tumor cell apoptosis by inhibition of downstream products such as small GTP-binding proteins, Rho, Ras and Rac, which are dependent on isoprenylation. Statins reduce angiogenesis in tumors by down-regulation of pro-angiogenic factors, such as vascular endothelial growth factor. In this review, the feasibility and efficacy of statins in the prevention and treatment of lung cancer are discussed.