ELR+ CXC chemokines in human milk

CXC chemokines bearing the glutamic acid-leucine-arginine (ELR) motif are crucial mediators in neutrophil-dependent acute inflammation. Interestingly, however, Interleukin (IL)-8/CXC ligand (CXCL) 8 is expressed in human milk in biologically significant concentrations, and may play a local maturational role in the developing human intestine. In this chemokine subfamily, there are six other known peptides beside IL-8/CXCL8, all sharing similar effects on neutrophil chemotaxis and angiogenesis. In this study, we measured the concentrations of these chemokines in human milk, sought their presence in human mammary tissue by immunohistochemistry, and confirmed chemokine expression in cultured human mammary epithelial cells (HMECs). Each of the seven ELR(+) CXC chemokines was measurable in milk, and except for NAP-2/CXCL7, these concentrations were higher than serum. The concentrations were higher in colostrum (except for GRO-beta/CXCL2 and NAP-2/CXCL7), and correlated negatively with time elapsed postpartum. IL-8/CXCL8, GRO-gamma/CXCL3, and ENA-78/CXCL5 concentrations were higher in preterm milk. There was intense immunoreactivity in mammary epithelial cells for all ELR(+) CXC chemokines, and the intensity of staining was higher in breast tissue with lactational changes. The supernatants from confluent HMEC cultures also contained measurable concentrations of all the seven ELR(+) CXC chemokines. These results confirm that all ELR(+) CXC chemokines are actively secreted by the mammary epithelial cells into human milk. Further studies are needed to determine if these chemokines share with IL-8/CXCL8 the protective effects on intestinal epithelial cells.     

MiRNA调控非小细胞肺癌转移的研究进展

微小RNA是内源性的非编码小RNA分子,通过与靶mRNA的结合在转录后水平调控基因的表达,从而参与众多生命活动的调控。NSCLC是严重威胁人类健康的恶性肿瘤,侵袭转移是其主要特征,也是其治疗失败和死亡的主要原因。miRNA可以通过促进上皮-间质转化、金属基质蛋白酶表达,以及血管生成来促进NSCLC转移,而且miRNA在调节肺癌干细胞特性中也发挥着重要作用。转移相关的miRNA已成为肺癌靶向治疗的新靶点。     

Blastomyces dermatitidis serine protease dipeptidyl peptidase IVA (DppIVA) cleaves ELR+CXC chemokines altering their effects on neutrophils

Blastomycosis elicits a pyogranulomatous inflammatory response that involves a prominent recruitment of neutrophils to the site of infection. Although neutrophils are efficiently recruited to the site of infection, this event is paradoxically coupled with the host's inability to control infection by Blastomyces dermatitidis, the causative agent. The mechanisms underlying this characteristic pyogranulomatous response and inability of neutrophils to kill the yeast are poorly understood. We recently reported that the fungal protease dipeptidyl peptidase IVA (DppIVA) promotes B. dermatitidis virulence by cleaving a dipeptide from the N‐terminus of C–C chemokines and granulocyte/macrophage‐colony stimulating factor, thereby inactivating them. Herein, we present evidence that DppIVA can also truncate the N‐terminus of members of the ELR⁺CXC chemokine family, which are known to modulate neutrophil function. We show that the DppIVA cleaved form of human (h) CXCL‐2, for example, hCXCL‐2 (3‐73), is a more potent neutrophil chemoattractant than its intact counterpart, but hCXCL‐2 (3‐73) is conversely impaired in its ability to prime the reactive oxygen species response of neutrophils. Thus, DppIVA action on ELR⁺CXC chemokines may promote the pyogranulomatous response that is typical of blastomycosis, while also explaining the inability of neutrophils to control infection.     

The expression and role of CXC chemokines in colorectal cancer

Cancer is a life-threatening disease world-wide and colorectal cancer is the second common cause of cancer mortality. The interaction between tumor cells and stromal cells plays a crucial role in tumor initiation and progression and is partially mediated by chemokines. Chemokines predominantly participate in the chemoattraction of leukocytes to inflammatory sites. Nowadays, it is clear that CXC chemokines and their receptors (CXCR) may also modulate tumor behavior by several important mechanisms: regulation of angiogenesis, activation of a tumor-specific immune response by attracting leukocytes, stimulation of tumor cell proliferation and metastasis. Here, we review the expression and complex roles of CXC chemokines (CXCL1 to CXCL16) and their receptors (CXCR1 to CXCR6) in colorectal cancer. Overall, increased expression levels of CXC chemokines correlate with poor prognosis.     

CXCL5 regulation of proliferation and migration in human non-small cell lung cancer cells

Epithelial neutrophil-activating peptide-78 (CXCL5), a member of the subgroup of CXC-type chemokine family, is an inflammatory factor involved in the progression of lung cancer, but the underlying mechanism remains unclear. In this study, we investigated the effects of CXCL5 on proliferation and migration in non-small cell lung cancer (NSCLC) using tissue microarrays from NSCLC patients and H460 cells transfected with a CXCL5-interfered lentivirus vector or stimulated with recombinant CXCL5. We observed that the expression of CXCL5 was significantly higher in lung cancer cell lines, and high CXCL5 was associated with high chemokine (C-X-C motif) receptor 2 expression and was significantly associated with poor differentiation. The high expression of CXCL5 was associated with poor NSCLC prognosis and was an independent predictive factor. Furthermore, downregulation of CXCL5 in H460 cells significantly reduced proliferation and migration. Recombinant CXCL5 promoted H460 cell proliferation and movement by activating MAPK/ERK1/2 and PI3K/AKT signaling. Our study elucidates the important role of CXCL5 in the progression and prognosis of NSCLC. These findings suggested that CXCL5 might be a potential biomarker and novel therapeutic target for lung cancer.     

榄香烯治疗非小细胞肺癌的作用机制研究进展

榄香烯注射液是从天然中草药姜科植物温郁金中提取获得的萜烯类化合物,其主要生物学活性为降低肿瘤细胞有丝分裂能力,诱导肿瘤细胞凋亡,抑制肿瘤细胞的生长,从而改善NSCLC患者的临床症状,增强患者免疫力.本文主要从杀灭癌细胞、诱导癌细胞凋亡、抑制癌细胞血管形成、增强患者免疫力等几方面综述榄香烯注射液对非小细胞肺癌的作用机制.     

Erlotinib in the treatment of non-small cell lung cancer

Because erlotinib, an epidermal growth factor receptor tyrosine kinase (EGFRTK) inhibitor, has been shown to be effective and well-tolerated as a second/third-line treatment in the therapy of advanced non-small cell lung cancer (NSCLC), this agent has been recently approved for human NSCLC therapy in the European Union. Although additive and synergistic effects of erlotinib and conventional chemotherapy were demonstrated in the combined regime preclinically, this has yet to be approved in the clinic. Since erlotinib and cytotoxic drugs have different biological targets, they have distinct side effects as well: erlotinib has no toxic effect on the bone marrow, but can cause diarrhea and rash, the latter being thought to be an indicator of the therapeutic efficacy. Several ongoing clinical trials are investigating the potential role of erlotinib in different settings in human NSCLC. This review intends to integrate our current knowledge on the erlotinib treatment in NSCLC.     

Epigenetics and cell cycle regulation in cystogenesis

The role of genetic mutations in the development of polycystic kidney disease (PKD), such as alterations in PKD1 and PKD2 genes in autosomal dominant PKD (ADPKD), is well understood. However, the significance of epigenetic mechanisms in the progression of PKD remains unclear and is increasingly being investigated. The term of epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. Epigenetic information can be inherited during mammalian cell division to sustain phenotype specifically and physiologically responsive gene expression in the progeny cells. A multitude of functional studies of epigenetic modifiers and systematic genome-wide mapping of epigenetic marks reveal the importance of epigenomic mechanisms, including DNA methylation, histone/chromatin modifications and non-coding RNAs, in PKD pathologies. Deregulated proliferation is a characteristic feature of cystic renal epithelial cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cyst formation and progression. Recent evidence suggests that alterations of DNA methylation and histone modifications on specific genes and the whole genome involved in cell cycle regulation and contribute to the pathogenesis of PKD. This review summarizes the recent advances of epigenetic mechanisms in PKD, which helps us to define the term of “PKD epigenetics” and group PKD epigenetic changes in three categories. In particularly, this review focuses on the interplay of epigenetic mechanisms with cell cycle regulation during normal cell cycle progression and cystic cell proliferation, and discusses the potential to detect and quantify DNA methylation from body fluids as diagnostic/prognostic biomarkers. Collectively, this review provides concepts and examples of epigenetics in cell cycle regulation to reveal a broad view of different aspects of epigenetics in biology and PKD, which may facilitate to identify possible novel therapeutic intervention points and to explore epigenetic biomarkers in PKD.     

CD10 expression in non-small cell lung cancer.

CD10 is a cell surface endopeptidase that inactivates various potentially growth stimulatory peptides. In lung cancer cell lines this downregulation has been associated with increased proliferation. Downregulation of CD10 in lung cancer tissue is described, suggesting a potential role in carcinogenesis and a possible use of CD10 as a prognostic marker. We aimed to determine the rate of CD10 expression in our non-small cell lung cancer (NSCLC) collection and to clarify its correlation with clinicopathological parameters and patient survival. 114 NSCLC were analysed immunohistochemically using a monoclonal CD10 antibody (clone NCL-CD10-270) on an NSCLC tissue micro array. The staining was semiquantitatively scored. CD10 expression was observed in 19% of cases, without any significant association with tumour type, -size, -grading, nodal status, clinical stage, and patient survival time. We conclude that a diagnostic use of CD10 immunostaining in NSCLC is unlikely.     

Concomitant hypermethylation of multiple genes in non-small cell lung cancer (NSCLC)

Primary lung cancer remains the leading cause of cancer death worldwide. Promoter hypermethylation is a major inactivation mechanism of tumor-related genes, and increasingly appears to play an important role in carcinogenesis. In the present study, we used quantitative methylation-specific PCR (Q-MSP) assays to analyze promoter hypermethylation of nine genes in a large cohort of well-characterized non-small cell lung cancer (NSCLC) and explore their associations with the clinicopathological features of tumor. We found that there were significant differences in methylation levels for six of nine gene promoters between cancerous and noncancerous lung tissues. More importantly, with 100% diagnostic specificity, high sensitivity, ranging from 44.9% to 84.1%, was found for each of the nine genes. Interestingly, promoter hypermethylation of most genes was closely associated with histologic type, which was more frequent in squamous cell carcinomas (SCC) than in adenocarcinomas (ADC). In addition, highly frequent concomitant methylation of multiple genes was found in NSCLC, particularly in SCC. Our data showed that multiple genes were aberrantly methylated in lung tumorigenesis, and that they were closely associated with certain clinicopathological features of NSCLC, particularly of the histologic type, suggesting that these hypermethylated genes could be potential biomarkers in early detection of NSCLC in high-risk individuals, as well as in evaluating the prognosis of NSCLC patients.     

Cardiac glycosides induce autophagy in human non-small cell lung cancer cells through regulation of dual signaling pathways

Na(+)/K(+)-ATPase targeted cancer therapy has attracted increasing interests of oncologists in lung cancer field. Although multiple anti-cancer mechanisms of cardiac glycosides as Na(+)/K(+)-ATPase inhibitors are revealed, the role of autophagy and related molecular signaling pathway for the class of compounds in human non-small cell lung cancer (NSCLC) cells has not been systematically examined. We herein investigated the anti-cancer effects of two representative cardiac glycosides, digoxin and ouabain, in A549 and H460 cell lines. Both agents caused significant growth inhibition at nanomolar level. The cardiac glycosides were found to induce moderate G(2)/M arrest but not apoptosis at IC(50) level in the NSCLC cell lines. Moreover, autophagy was markedly induced by both agents, as evidenced by the time- and dose-dependent increase of LC3-II, up-regulation of Atg5 and Beclin1, as well as by the observations through acridine orange staining, transmission electron microscopy and quantification of GFP-LC3 fluorescence. Importantly, AMP-activated protein kinase (AMPK) pathway was activated, resulting in mammalian target of rapamycin (mTOR) deactivation during autophagy induction. Moreover, extracellular-signal-regulated kinase 1/2 (ERK1/2) activation was simultaneously found to be involved in the autophagy regulation. Co-treatment with respective inhibitors or siRNAs could either block the autophagic phenotypes and signals, or significantly increase the cellular viability, indicating the drugs-induced autophagy plays tumor-suppressing role. This work provides first evidence showing that the cardiac glycosides induce autophagy in human NSCLC cells through regulation of both mTOR and ERK1/2 signaling pathways. The autophagy may at least partially account for the growth inhibitory effects of the compounds in human NSCLC cells.