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TP53/miR-34a-associated signaling targets SERPINE1 expression in human pancreatic cancer.

TP53/miR-34a-associated 信号靶向 SERPINE1 在人胰腺癌中的表达。

  • 影响因子:5.5150
  • DOI:10.18632/aging.102776
  • 作者列表:"Akula SM","Ruvolo PP","McCubrey JA
  • 发表时间:2020-01-27
Abstract

:Pancreatic ductal adenocarcinoma (PDAC) is a disease of aging. The TP53 gene product regulates cell growth, aging, and cancer. To determine the important targets of TP53 in PDAC, we examined the expression of 440 proteins on a reverse phase protein array (RPPA) in PDAC-derived MIA-PaCa-2 cells which either had WT-TP53 or lacked WT-TP53. MIA-PaCa-2 cells have a TP53 mutation as well as mutant KRAS and represent a good in vitro model to study PDAC. RPPA analysis demonstrated expression of tumor promoting proteins in cells that lacked WT-TP53; and this feature could be reversed significantly when the cells were transfected with vector encoding WT-TP53 or treated with berberine or a modified berberine (BBR). Expression of miR-34a-associated signaling was elevated in cells expressing WT-TP53 compared to cells expressing mTP53. Results from in vivo studies using human PDAC specimens confirmed the in vitro results as the expression of miR-34a and associated signaling was significantly decreased in PDAC specimens compared to non-cancerous tissues. This study determined SERPINE1 as a miR-34a target with relevance to the biology of PDAC. Thus, we have identified a key target (SERPINE1) of the TP53/miR-34a axis that may serve as a potential biomarker for early detection of pancreatic cancer.

摘要

: 胰腺导管腺癌 (PDAC) 是一种衰老性疾病。TP53 基因产物调节细胞生长、衰老和癌症。为了确定 PDAC 中 TP53 的重要靶点,我们在 MIA-PaCa-2 或缺乏 WT-TP53 的 PDAC 来源的 WT-TP53 细胞中检测了 440 个蛋白在反相蛋白阵列 (RPPA) 上的表达。MIA-PaCa-2 细胞具有 TP53 突变和 KRAS 突变,是研究 PDAC 的良好体外模型。RPPA 分析显示肿瘤促进蛋白在缺乏 WT-TP53 的细胞中表达; 当细胞转染编码 WT-TP53 的载体或用小檗碱或改良的小檗碱 (BBR) 处理后,这一特征可显著逆转。与表达 mtp53 的细胞相比,表达 miR-34a-associated 的细胞中 WT-TP53 信号的表达升高。使用人 PDAC 标本的体内研究结果证实了体外结果,因为与非癌组织相比,PDAC 标本中 miR-34a 和相关信号的表达显著降低。本研究确定 SERPINE1 为与 PDAC 生物学相关的 miR-34a 靶点。因此,我们确定了 TP53/miR-34a 轴的一个关键靶点 (SERPINE1),可以作为胰腺癌早期检测的潜在生物标志物。

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相关文献
影响因子:5.5150
发表时间:2020-01-27
来源期刊:Aging
DOI:10.18632/aging.102776
作者列表:["Akula SM","Ruvolo PP","McCubrey JA"]

METHODS::Pancreatic ductal adenocarcinoma (PDAC) is a disease of aging. The TP53 gene product regulates cell growth, aging, and cancer. To determine the important targets of TP53 in PDAC, we examined the expression of 440 proteins on a reverse phase protein array (RPPA) in PDAC-derived MIA-PaCa-2 cells which either had WT-TP53 or lacked WT-TP53. MIA-PaCa-2 cells have a TP53 mutation as well as mutant KRAS and represent a good in vitro model to study PDAC. RPPA analysis demonstrated expression of tumor promoting proteins in cells that lacked WT-TP53; and this feature could be reversed significantly when the cells were transfected with vector encoding WT-TP53 or treated with berberine or a modified berberine (BBR). Expression of miR-34a-associated signaling was elevated in cells expressing WT-TP53 compared to cells expressing mTP53. Results from in vivo studies using human PDAC specimens confirmed the in vitro results as the expression of miR-34a and associated signaling was significantly decreased in PDAC specimens compared to non-cancerous tissues. This study determined SERPINE1 as a miR-34a target with relevance to the biology of PDAC. Thus, we have identified a key target (SERPINE1) of the TP53/miR-34a axis that may serve as a potential biomarker for early detection of pancreatic cancer.

翻译标题与摘要 下载文献
影响因子:5.13
发表时间:2020-01-28
DOI:10.1080/17425247.2020.1723544
作者列表:["Kou L","Huang H","Lin X","Jiang X","Bao S","Luo Q","Sun J","Yao Q","Ganapathy V","Chen R"]

METHODS::Background: SLC6A14 (ATB0,+), a Na+/Cl-coupled transporter for neutral/cationic amino acids, is overexpressed in many cancers; It has been investigated as a target for improved liposomal drug delivery to treat liver cancer.Research design and methods: Here we explored the mechanism of ATB0,+-mediated entry of such liposomes. As ATB0,+ is highly-expressed in pancreatic cancer, we also examined the therapeutic utility of ATB0,+-targeted liposomal drug delivery to treat this cancer.Results: The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB0,+-positive MCF7 cells. The uptake process consisted of two steps: binding and internalization. The binding of LYS-LPs to MCF7 cells was higher than that of bare liposomes, and the process was dependent on Na+ and Cl-, and inhibitable by ATB0,+ substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB0,+ occurred via endocytosis with transient endosomal degradation of ATB0,+ protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB0,+-dependent manner.Conclusions: We conclude that ATB0,+ could be exploited for targeted drug delivery in the form of lysine-conjugated liposomes and that the approach represents a novel strategy for enhanced pancreatic cancer therapy.

翻译标题与摘要 下载文献
影响因子:2.30
发表时间:2020-01-28
DOI:10.1007/s00423-020-01857-4
作者列表:["Okada KI","Kawai M","Hirono S","Kojima F","Tanioka K","Terada M","Miyazawa M","Kitahata Y","Iwahashi Y","Ueno M","Hayami S","Murata SI","Shimokawa T","Yamaue H"]

METHODS:PURPOSE:Pre-operative prediction of histological response to neoadjuvant therapy aids decisions regarding surgical management of borderline resectable pancreatic cancer (BRPC). We elucidate correlation between pre-/post-treatment whole-tumor apparent diffusion coefficient (ADC) value and rate of tumor cell destruction. We newly verify whether post-treatment ADC value at the site of vascular contact predicts R0 resectability of BRPC. METHODS:We prospectively reviewed 28 patients with BRPC who underwent diffusion-weighted magnetic resonance imaging before neoadjuvant chemotherapy and surgery. Correlation between the percentage of tumor cell destruction and various parameters was analyzed. Strong parameters were assessed for their ability to predict therapeutic histological response and R0 resectability. RESULTS:Pre-/post-treatment whole-tumor ADC value correlated with tumor cell destruction rate by all parameters (R = 0.630/0.714, P  50% was determined at 1.40 × 10-3 mm2/s. It predicts histological response with 100% sensitivity, 81% specificity, and 89% accuracy. It predicts R0 with 88% sensitivity, 70% specificity, and 75% accuracy. CONCLUSIONS:Post-treatment whole-tumor ADC value may be a predictor of R0 resectability in patients with BRPC. Tumor cell destruction rate is indicated by the difference between pre-/post-treatment ADC values. This difference is strongly affected by the pre-treatment ADC value. The cutoff value of ADC at the site of vascular contact could not discriminate R0 resectability.

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