1,729,886 research outputs found
miR-4484 suppresses hepatocellular carcinoma progression via targeting KIF2C
No full textAberrantly expressed microRNA-4484 (miR-4484) has recently garnered attention for its involvement in human diseases, but its specific role in hepatocellular carcinoma (HCC) remains largely unexplored. This study investigates the function of miR-4484 in HCC progression and its regulatory interaction with KIF2C. Analysis of the data from the TCGA-LIHC database revealed that miR-4484 expression is significantly downregulated in HCC tissues, with lower levels correlating with worse prognosis. In vitro experiments confirmed that miR-4484 expression is lower in HCC cell lines compared to a normal liver cell line. Functional assays demonstrated that miR-4484 overexpression via a miR-4484 mimic suppressed cell proliferation and induced G1 phase arrest, whereas miR-4484 inhibition promoted proliferation and facilitated cell cycle progression from G1 to S and G2 phases. Additionally, KIF2C expression was significantly upregulated in HCC tissues and cell lines, exhibiting an inverse correlation with miR-4484 levels. Dual-Luciferase Reporter Assays confirmed that miR-4484 directly binds to KIF2C, thereby regulating its expression and influencing cell proliferation and cell cycle progression. In vivo, subcutaneous intratumoral injection of the miR-4484 mimic in nude mice significantly inhibited HCC tumour growth. These findings highlight miR-4484 as a potential tumour suppressor in HCC through its direct targeting of KIF2C, underscoring its promise as a therapeutic target for HCC treatment
MicroRNA in mitochondria and the effects of miR-4484 in a drug resistant cancer line with P-glycoprotein expression
No full textM.Phil.Cancer is one of the most death-causing diseases worldwide. Cancer cells always develop multidrug resistance (MDR) after long time exposure to anti-cancer drugs. MDR severely hampers the efficiency of chemotherapy. The expression of P-glycoproteins (P-gp), which can efflux different anti-cancer drugs, are one of the many mechanisms of MDR.MicroRNAs (miRNAs) together with Argonaute (Ago) protein are essential for post-transcriptional gene regulation. Growing evidence suggested that nuclear-encoded miRNAs are imported to the mitochondria. Despite their existence, their biogenesis and action mechanisms remain unexplored. This project aims at investigating the relationships between miRNAs and MDR. The hypothesis in my project is that miRNAs found inside the mitochondria can reverse MDR.In my project, HepG2 and R-HepG2 were used as a model to study MDR. R-HepG2 cells were less susceptible to doxorubicin (Dox) toxicity compared to HepG2 cells. The expression of P-gp in R-HepG2 cells facilitated the removal of Dox. R-HepG2 cells retained its MDR property when treated with glucose free medium supplemented with galactose while the addition of ETC inhibitors significantly elevated the intracellular concentration of Dox.Affinity column was used to extract mitochondria which purity was checked by Western blotting and PCR. We discovered miR-4461, miR-4484 and miR-4485 were present in the mitochondria of both HepG2 and R-HepG2 cell lines. In particular, the relative expression level of miR-4484 was 2.5-fold higher in the mitochondria of R-HepG2 than that of HepG2. Also, Ago 2 protein was detected in the isolated mitochondria. Although in silico prediction by RNAhybrid and miRWalk2.0 demonstrated a perfect complementary of the seed region of miR-4484 and the cytochrome b (Cyb) mRNA, there was no significant changes in the amount of Cyb after transfection of miR-4484.Nevertheless, the expression level of miR-4484 in HepG2 cells escalated in a dose-dependent manner when treated with Dox but did not change in R-HepG2 cells. Intriguingly, P-gp increased in R-HepG2 cells transfected with miR-4484 compared to its counterpart transfected with a scramble siRNA as negative control while P-gp could not be detected in transfected HepG2 cells. However, there was no significant difference in P-gp mRNA between miR-4484 transfected R-HepG2 cells and negative control. Unexpectedly, R-HepG2 cells incubated with Dox for 2, 4 and 6 hours after miR-4484 transfection for 48 hours did not show a reduction in Dox uptake comparing to the negative control. We demonstrated that miR-4484 found inside the mitochondria could not reverse MDR by reducing Dox uptake.Future experiments can be performed to investigate how do miRNA being specifically transported to the mitochondria and exert their functions. Since we have not confirmed the physiological role of miR-4484, high throughput RNA sequencing can help us to identify the targets regulated directly by miR-4484. We observed that elevation of P-gp did not promote drug efflux. Further studies can be done to examine whether these P-gps have proper post-translational modifications or they are not targeted to the cell membrane but trapped inside the cell. Our research may provide new evidence to study mitochondrial miRNAs and insight for using miRNA to reverse MDR.癌症是全球最致命的疾病之一。縱然有新化學治療藥物, 長時間使用抗癌藥物可引致多腫瘤細胞產生多重抗藥性(multidrug resistance)，從而減低化療效用。在癌細胞膜上表達P-糖蛋白 (p-glycoprotein) 可以排出多種抗癌藥物是其中一種多重抗藥性機制。小分子核糖核酸 (microRNA)與Argonaute (Ago) 蛋白對轉錄後基因調控非常重要。證據顯示核編碼的小分子核糖核酸可被導入線粒體，但它們的生源和作用機制仍未得到探索。 此項目旨在研究小分子核糖核酸與多重抗藥性之間的關係。 我們假設在線粒體內發現的小分子核糖核酸可以逆轉多重抗藥性。此項研究以HepG2和R-HepG2細胞作研究多重抗藥性模型。阿黴素(doxorubicin) 對 R-HepG2細胞的毒性較低。 P-糖蛋白能夠移除細胞中的阿黴素。當用無葡萄糖培養基處理時，R-HepG2細胞保存了多重抗藥性的特性，然而電子傳遞鏈抑製劑則增加了R-HepG2細胞內的阿黴素。我們以親和層析法提取線粒體，並以西方墨點法和聚合酶連鎖反應檢查其純度。我們於HepG2和R-HepG2細胞系的線粒體中發現miR-4461、miR-4484和miR-4485。R-HepG2線粒體中miR-4484的數量比HepG2高2.5倍。此外，在分離的線粒體中能檢測到Ago 2蛋白。雖然RNAhybrid和miRWalk2.0預測miR-4484的種子區域和細胞色素b (cytochrome b) mRNA完美互補，但是轉染miR-4484後卻沒有改變細胞色素b的數目。當用阿黴素處理時，HepG2細胞中miR-4484的數量以劑量依賴性方式升高，在R-HepG2細胞中卻沒有變化。P-糖蛋白的數量在轉染miR-4484的R-HepG2細胞較以scramble siRNA轉染的為多，而被轉染的HepG2細胞中並未檢測到任何P-糖蛋白。然而，miR-4484轉染的R-HepG2細胞和陰性對照之間的P-糖蛋白信使核糖核酸 (mRNA) 則沒有顯著差異。在miR-4484轉染48小時後再經阿黴素處理2、4和6小時的R-HepG2細胞並沒有減少阿黴素攝取。實驗結果顯示在線粒體內發現的miR-4484不能增加阿黴素攝取來逆轉多重抗藥性。未來研究方向包括小分子核糖核酸如何被轉運至線粒體並發揮其功能。我們尚未證實miR-4484的生理作用，因此高通量測序可幫助我們識別miR-4484直接調控的信使核糖核酸。鑑於增加P-糖蛋白不能促進藥物外排，我們可以進一步研究這些P-糖蛋是否具有適當的翻譯後修飾，或者它們是否在細胞膜上表達。我們的結果可以為研究線粒體小分子核糖核酸和逆轉多重抗藥性提供新的線索。Lam, Shing Fung."December 2018."Thesis M.Phil. Chinese University of Hong Kong 2019.Includes bibliographical references (leaves 129-151).Abstracts also in Chinese.Title from PDF title page (viewed on …)
The constitutive relation and small scale parameter of nonlocal continuum mechanics for modelling carbon nanotubes
No full text10.1088/0957-4484/18/7/075702Nanotechnology187-NNOT
Vibration of nonlocal Timoshenko beams
No full text10.1088/0957-4484/18/10/105401Nanotechnology1810-NNOT
Nonlinear bending and stretching of a circular graphene sheet under a central point load
No full text10.1088/0957-4484/20/7/075702Nanotechnology207-NNOT
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Impact of somatic copy number alterations on the glioblastoma miRNome: miR-4484 is a genomically deleted tumour suppressor
No full textGlioblastoma (GBM) is the most frequent and most malignant primary brain tumour in adults. GBMs have a unique landscape of somatic copy number alterations (SCNAs), with the concomitant appearance of numerous driver amplifications and deletions. Here, we examined the genomic regions harbouring SCNAs and their impact on the GBM miRNome. We found that 40% of SCNA events covering 70-88% of the genomically altered regions, as identified by GISTIC and RAE algorithms, carried miRNA genes. Of 1426 annotated mature miRNAs analysed, similar to 14% (n = 198) were mapped to such fragile loci. Further, we identified an intragenic miRNA, miR-4484 located on chromosome-10, as a deleted and downregulated miRNA in GBM. miR-4484 exhibited a strong positive correlation with the expression of its host gene uroporphyrinogen III synthase (UROS), thereby indicating that the loss of miR-4484 is a codeletion event in GBM. Overexpression of miR-4484 reduced the colony-forming ability and suppressed the migratory capacity of glioma cells. Analysis of the RNA-seq-derived transcriptome upon exogenous miR-4484 overexpression in conjunction with an integrative bioinformatics approach revealed several putative targets of miR-4484. Unbiased functional enrichment of these targets through DAVID identified a cohort of important gene ontology terms, which possibly explain the functional role of miR-4484 in gliomagenesis. Selected targets were validated and, importantly, were found to be upregulated in GBM. In brief, our study identified a panel of miRNAs that are likely to be regulated by genomic deletions and amplifications. Further, miR-4484 was found to be deleted and acts as a tumour suppressor miRNA in GBM
Product moment correlations between all study variables in 2006 (n = 4484).
No full text<p>Product moment correlations between all study variables in 2006 (n = 4484).</p
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