AXL表达与乳腺癌预后及临床病理特征关系的Meta分析

目的 探讨受体酪氨酸激酶AXL蛋白的表达对乳腺癌患者预后及临床病理特征的意义。方法 在中国知网(CNKI)、万方医学网(Wanfang Data)、 Cochrane Library、Embase、PubMed和Medline数据库中,搜索国内外公开发表的有关AXL与乳腺癌预后关系的文献,检索时限均为从建库至2019年10月。2位研究者按纳入和排除标准独立筛选文献、提取资料和评价纳入研究的偏倚风险,并进行Meta分析。结果 共纳入7篇文献,包括933例乳腺癌患者。AXL高表达组的乳腺癌患者总生存期(overall survival,OS)明显低于低表达组(HR=2.36,95%CI 1.60~3.46,P<0.000 1),但其表达在无复发生存期(relapse free survival,RFS)和无疾病生存期(disease free survival,DFS)中差异无统计学意义,且与乳腺癌的年龄、临床分期、组织分级、淋巴结转移及受体表达的相关性分析无统计学意义。结论 AXL的阳性表达与乳腺癌患者预后不良有关,是乳腺癌个体化治疗的潜在分子标志物。     

AXL receptor tyrosine kinase is increased in patients with heart failure

Background

AXL is a membrane receptor tyrosine kinase highly expressed in the heart and has a conspicuous role in cardiovascular physiology. The role of AXL in heart failure (HF) has not been previously addressed.

Methods and results

AXL protein was enhanced 6-fold in myocardial biopsies of end-stage HF patients undergoing heart transplantation compared to controls from heart donors (P < 0.0001). Next, we performed a transversal study of patients with chronic HF (n = 192) and a group of controls with no HF (n = 67). sAXL and BNP circulating levels were quantified and clinical and demographic data were collected.sAXL levels in serum were higher in HF (86.3 ± 2.0 ng/mL) than in controls (67.8 ± 2.0 ng/mL; P < 0.0001). Also, sAXL correlated with several parameters associated with worse prognosis in HF. Linear regression analysis indicated that serum creatinine, systolic blood pressure and atrial fibrillation, but not BNP levels, were predictive of sAXL levels. Cox regression analysis indicated that high sAXL values at enrollment time were related to the major HF events (all-cause mortality, heart transplantation and HF hospitalizations) at one year follow-up (P < 0.001), adding predictive value to high BNP levels.

Conclusions

Myocardial expression and serum concentration of AXL is elevated in HF patients compared to controls. Furthermore, peripheral sAXL correlates with parameters associated with the progression of HF and with HF events at short term follow-up. All together these results suggest that sAXL could belong to a new molecular pathway involved in myocardial damage in HF, independent from BNP.     

Soluble AXL is ubiquitously present in malignant serous effusions

Objective

The objective of this study was to analyze the expression level and clinical role of soluble AXL (sAXL) in cancers affecting the serosal surfaces, with focus on ovarian carcinoma.

AXL在肿瘤转移和耐药中的作用及干预策略研究进展

AXL是酪氨酸激酶受体之一,在恶性肿瘤细胞中高表达,并通过多种信号传导途径,尤其是与EMT形成正向反馈循环,促进肿瘤转移和耐药,成为肿瘤治疗的一个新靶点。通过抑制AXL的表达可有效逆转EMT和肿瘤转移与耐药。     

MicroRNA-139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL

Background: We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using next-generation sequencing-based whole miRNome sequencing and quantitative polymerase chain reaction-based validation analysis. In this study, we examined the mechanism of action of miR-139-5p, one of the downregulated miRNAs identified in the panel. Methods: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR-139 (dichotomized around the median) using the Kaplan-Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR-139 to confirm its targets as well as examine pathways through which miR-139 may function using cell-based assays. Results: Low miR-139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR-139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR-139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR-139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33-0.82). Overexpression of miR-139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR-139 based on multiple miRNA-binding sites in 3′-untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR-139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR-139 treatment, which was reversed by the addition of miR-139 antagomir. Examination of the molecular mechanism of growth inhibition by miR-139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21. Conclusions: miR-139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components.     

酪氨酸激酶受体表达水平对上皮性卵巢癌细胞侵袭性的影响及其机制

目的探讨AXL表达水平与上皮性卵巢癌细胞侵袭性的关系及其机制。方法使用OVCAR3细胞为研究载体,通过siRNA干扰细胞中AXL的表达,通过RT-PCR检测两组细胞中AXL以及MMP-9基因表达水平,Transwell法比较干扰组细胞与对照组细胞侵袭能力,并比较siRNA干扰组细胞与对照组细胞在裸鼠体内的成瘤能力。结果干扰组OVCAR3细胞中AXL以及基质金属蛋白酶-9表达水平明显降低,差异有统计学意义(P<0.05);实施siRNA转染组细胞侵袭细胞数量为73±10.5个,明显低于对照组261.5±21.7个,差异有统计学意义(P<0.05);干扰组细胞裸鼠成瘤的质量以及肿瘤细胞的数量均明显低于对照组,差异有统计学意义(P<0.05)。结论 AXL表达抑制时可能通过减少细胞内基质金属蛋白酶-9的mRNA的表达降低上皮性卵巢细胞的侵袭能力。     

ShcC proteins: Brain aging and beyond

To date, most studies of Shc family of signaling adaptor proteins have been focused on the near-ubiquitously expressed ShcA, indicating its relevance to age-related diseases and longevity. Although the role of the neuronal ShcC protein is much less investigated, accumulated evidence suggests its importance for neuroprotection against such aging-associated conditions as brain ischemia and oxidative stress. Here, we summarize more than decade of studies on the ShcC expression and function in normal brain, age-related brain pathologies and immune disorders with a focus on the interactions of ShcC with signaling proteins/pathways, and the possible implications of these interactions for changes associated with aging.     

Therapeutic activity of DCC-2036, a novel tyrosine kinase inhibitor,against triple-negative breast cancer patient-derived xenografts by targeting AXL/MET

Triple-negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC-2036 inhibited the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC-2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC-2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC-2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt-NFκB signaling to exert its antitumor effect in TNBC. DCC-2036 also inhibited the growth and metastasis of xenografted MDA-MB-231 cells (AXL/MET-high TNBC cells) but not MDA-MB-468 cells (AXL-low TNBC cells) in NSG mice in vivo. Furthermore, DCC-2036 significantly inhibited tumor growth and invasion of AXL/MET-high TNBC PDX tumors but not AXL/MET-low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC-2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC-2036 even at a high dosage. Therefore, DCC-2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.     

AXL kinase as a novel target for cancer therapy

The AXL receptor tyrosine kinase and its major ligand, GAS6 have been demonstrated to be overexpressed and activated in many human cancers (such as lung, breast, and pancreatic cancer) and have been correlated with poor prognosis, promotion of increased invasiveness/metastasis, the EMT phenotype and drug resistance. Targeting AXL in different model systems with specific small molecule kinase inhibitors or antibodies alone or in combination with other drugs can lead to inactivation of AXL-mediated signaling pathways and can lead to regained drug sensitivity and improved therapeutic efficacy, defining AXL as a promising novel target for cancer therapeutics. This review highlights the data supporting AXL as a novel treatment candidate in a variety of cancers as well as the current status of drug development targeting the AXL/GAS6 axis and future perspectives in this emerging field.