Extracellular Vesicles: Messengers of p53 in Tumor–Stroma Communication and Cancer Metastasis

Tumor progression to a metastatic and ultimately lethal stage relies on a tumor-supporting microenvironment that is generated by reciprocal communication between tumor and stromal host cells. The tumor–stroma crosstalk is instructed by the genetic alterations of the tumor cells—the most frequent being mutations in the gene Tumor protein p53 (TP53) that are clinically correlated with metastasis, drug resistance and poor patient survival. The crucial mediators of tumor–stroma communication are tumor-derived extracellular vesicles (EVs), in particular exosomes, which operate both locally within the primary tumor and in distant organs, at pre-metastatic niches as the future sites of metastasis. Here, we review how wild-type and mutant p53 proteins control the secretion, size, and especially the RNA and protein cargo of tumor-derived EVs. We highlight how EVs extend the cell-autonomous tumor suppressive activity of wild-type p53 into the tumor microenvironment (TME), and how mutant p53 proteins switch EVs into oncogenic messengers that reprogram tumor–host communication within the entire organism so as to promote metastatic tumor cell dissemination.     

GAO Feng~1,LI Wei~2,TANG Zon

tific Experiment Center of Guangxi Medical University,Nanning 530021,China)Objective:To investigate the mutation pattern of adenomatous polyposis coli(APC),Kirsten-ras(K-ras) and p53 genes in sporadic colorectal cancer tissues.Meth     

Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.     

Potential Antitumor Effects of 6-Gingerol in p53-Dependent Mitochondrial Apoptosis and Inhibition of Tumor Sphere Formation in Breast Cancer Cells

Hormone-specific anticancer drugs for breast cancer treatment can cause serious side effects. Thus, treatment with natural compounds has been considered a better approach as this minimizes side effects and has multiple targets. 6-Gingerol is an active polyphenol in ginger with various modalities, including anticancer activity, although its mechanism of action remains unknown. Increases in the level of reactive oxygen species (ROS) can lead to DNA damage and the induction of DNA damage response (DDR) mechanism, leading to cell cycle arrest apoptosis and tumorsphere suppression. Epidermal growth factor receptor (EGFR) promotes tumor growth by stimulating signaling of downstream targets that in turn activates tumor protein 53 (p53) to promote apoptosis. Here we assessed the effect of 6-gingerol treatment on MDA-MB-231 and MCF-7 breast cancer cell lines. 6-Gingerol induced cellular and mitochondrial ROS that elevated DDR through ataxia-telangiectasia mutated and p53 activation. 6-Gingerol also induced G0/G1 cell cycle arrest and mitochondrial apoptosis by mediating the BAX/BCL-2 ratio and release of cytochrome c. It also exhibited a suppression ability of tumorsphere formation in breast cancer cells. EGFR/Src/STAT3 signaling was also determined to be responsible for p53 activation and that 6-gingerol induced p53-dependent intrinsic apoptosis in breast cancer cells. Therefore, 6-gingerol may be used as a candidate drug against hormone-dependent breast cancer cells.     

乳腺浸润性导管癌p53表达与腋窝淋巴结转移的相关性分析

为研究乳腺浸润性导管癌组织p53表达及腋窝淋巴结转移的相关性,作者利用免疫组化染色检测72例浸润性导管癌标本中p53的表达水平,分析p53表达及腋窝淋巴结转移的关系。得出结果:腋淋巴结转移组共37例(52%),p53阳性表达21例(57%);未转移组共35例(48%),p53阳性表达11例(31%),转移组p53阳性表达较未转移组明显增高(P0.05);淋巴结转移数1~3个25例(68%)、≥4个12例(32%),p53表达阳性分别是12例(48%)和8例(67%),p53表达阳性率与淋巴结转移数呈正相关(P0.05)。结果表明,通过检测乳腺浸润性导管癌组织中p53蛋白的表达水平可以判断腋窝淋巴结转移状况和愈后。     

MIL-53的合成和表征及储氢性能研究

采用水热合成法将对苯二甲酸（H2BDC）、水分别与Cr（NO3）3.9H2O、Al（NO3）3.9H2O混合后加热至220℃晶化3d,合成了具有三维立体网状骨架结构的有机金属骨架MIL-53（Cr）as与MIL-53（Al）as,将其分别在300、330℃下煅烧3d得到有机金属骨架MIL-53（Cr）ht与MIL-53（Al）ht。通过X射线衍射（XRD）、智能重量分析仪（IGA）、扫描电镜（SEM）、红外光谱仪（IR）和热重分析仪（TG）等表征手段系统地对它们的结构、组成以及储氢性能进行了研究。实验结果表明,有机金属骨架MIL-53系列独特的骨架呼吸特性使其具有良好的储氢性能,且具有较高比表面积、孔容及孔径的MIL-53（Al）在储氢性能方面具有更好的表现。     

p53抑癌基因电化学阻抗传感器研究

基于电化学阻抗技术构建了一种检测p53抑癌基因的电化学传感器.首先利用自组装作用将末端带巯基的探针p53抑癌基因(p53-DNA)固定于金电极表面,根据传感器结合前后电子转移阻抗值的变化,对目标p53-DNA进行了测定.以pH =7.4的5mmol/L K3[Fe(CN)6]-5mmol/L K4[Fe(CN)6]平衡电对溶液作为检测液,检测目标p53-DNA的线性浓度范围为1.0×10-8～ 1.0×10-6 mol/L,其检出限为3.0×10-9 mol/L(S/N =3).对5.0×10-8 mol/L的目标p53-DNA进行11次平行测定,其RSD为3.4％.该传感器制作简单、灵敏高、选择性好,且无需标记,易于操作.     

A survey of singular curves in sub-Riemannian geometry

Sub-Riemannian geometry is the geometry of a distribution ofk-planes on an-dimensional manifold with a smoothly varying inner product on thek-planes. Singular curves are singularities of the space of paths tangent to the distribution and joining two fixed points. This survey is devoted to the singular curves, which can be length minimizing geodesics, independent of the choice of inner product.