Range of HOX/TALE superclass associations and protein domain requirements for HOXA13:MEIS interaction

AbdB-like HOX proteins form DNA-binding complexes with the TALE superclass proteins MEIS1A and MEIS1B, and trimeric complexes have been identified in nuclear extracts that include a second TALE protein, PBX. Thus, soluble DNA-independent protein-protein complexes exist in mammals. The extent of HOX/TALE superclass interactions, protein structural requirements, and sites of in vivo cooperative interaction have not been fully explored. We show that Hoxa13 and Hoxd13 expression does not overlap with that of Meis1-3 in the developing limb; however, coexpression occurs in the developing male and female reproductive tracts (FRTs). We demonstrate that both HOXA13 and HOXD13 associate with MEIS1B in mammalian and yeast cells, and that HOXA13 can interact with all MEIS proteins but not more diverged TALE superclass members. In addition, the C-terminal domains (CTDs) of MEIS1A (18 amino acids) and MEIS1B (93 amino acids) are necessary for HOXA13 interaction; for MEIS1B, this domain was also sufficient. We also show by yeast two-hybrid assay that MEIS proteins can interact with anterior HOX proteins, but for some, additional N-terminal MEIS sequences are required for interaction. Using deletion mutants of HOXA13 and HOXD13, we provide evidence for multiple HOX peptide domains interacting with MEIS proteins. These data suggest that HOX:MEIS interactions may extend to non-AbdB-like HOX proteins in solution and that differences may exist in the MEIS peptide domains utilized by different HOX groups. Finally, the capability of multiple HOX domains to interact with MEIS C-terminal sequences implies greater complexity of the HOX:MEIS protein-protein interactions and a larger role for variation of HOX amino-terminal sequences in specificity of function.     

The balance between leptin and adiponectin in the control of carcinogenesis - Focus on mammary tumorigenesis

A number of studies indicate that a growing list of cancers may be influenced by obesity. In obese individuals these cancers can be more frequent and more aggressive resulting in reduced survival. One of the most prominent and well characterized cancers in this regard is breast cancer. Obesity plays a complex role in breast cancer and is associated with increased inflammation, angiogenesis and alterations in serum levels of potential growth factors such as insulin, adiponectin, leptin and estrogen. Reduced levels of serum adiponectin have been reported in breast cancer patients compared to healthy controls, particularly in postmenopausal women and the level of adiponectin has been shown to be inversely associated with insulin resistance. The role of serum leptin levels in breast cancer appears to be more complex. Some studies have shown leptin to be increased in women with breast cancer but other studies have found leptin to be decreased or unchanged. This may be due to a number of confounding issues. We and others propose that it may be the levels of adiponectin and leptin as well as the balance of adiponectin and leptin that are the critical factors in breast and other obesity related cancer tumorigenesis. This review will focus on the current understanding of the interplay between obesity and the functions of leptin and adiponectin. It will then examine what is known about their potential roles in cancer particularly as pertains to breast cancer and how the ratio of adiponectin to leptin may play a role in tumorigenesis.     

Hypermethylated and downregulated MEIS2 are involved in stemness properties and oxaliplatin-based chemotherapy resistance of colorectal cancer

The resistance against oxaliplatin (L-OHP) based regimens remains a major obstacle for its efficient usage in treating metastatic colorectal cancer (mCRC). In this study, we performed weighted gene coexpression network analysis (WGCNA) to systematically screen the relevant hub genes for L-OHP resistance using the raw microarray data of 30 consecutive mCRC samples from our earlier study (GSE69657). The results were further confirmed through datasets from Gene Expression Omnibus (GEO). From L-OHP resistance module, nine genes in both the coexpression and protein–protein interaction networks were chosen as hub genes. Among these genes, Meis Homeobox 2 (MEIS2) had the highest correlation with L-OHP resistance (r = −0.443) and was deregulated in L-OHP resistant tissues compared with L-OHP sensitive tissues in both our own dataset and GSE104645 testing dataset. The receiver operating characteristic curve validated that MEIS2 had a good ability in predicting L-OHP response in both our own dataset (area under the curve [AUC] = 0.802) and GSE104645 dataset (AUC = 0.746). Then, the down expression of MEIS2 was observed in CRC tissue compared with normal tissue in 12 GEO-sourced datasets and The Cancer Genome Atlas (TCGA) and was correlated with poor event-free survival. Furthermore, analyzing methylation data from TCGA showed that MEIS2 had increased promoter hypermethylation. In addition, MEIS2 expression was significantly decreased in CRC stem cells compared with nonstem cells in two GEO datasets (GSE14773 and GSE24747). Further methylation analysis from GSE104271 demonstrated that CRC stem cells had higher MEIS2 promoter methylation levels in cg00366722 and cg00610348 sites. Gene set enrichment analysis showed that MEIS2 might be involved in the Wnt/β-catenin pathway. In the overall view, MEIS2 had increased promoter hypermethylation and was downregulated in poor L-OHP response mCRC tissues. MEIS2 might be involved in the Wnt/β-catenin pathway to maintain CRC stemness, which leads to L-OHP resistance.     

Co-expression of fatty acid synthase and caveolin-1 in pancreatic ductal adenocarcinoma: Implications for tumor progression and clinical outcome

Pancreatic cancer is a devastating disease that afflicts over 35,000 Americans every year. Since therapeutic options are limited, understanding the molecular aspects of this disease is critical for moving towards targeted treatment of this aggressive form of cancer. Caveolin-1 (Cav-1) and fatty acid synthase (FASN) are two proteins that have been shown to be dysregulated in a number of cancers. Functionally these proteins have been shown to be involved in the process of tumorigenesis. We thus surveyed the expression of both these critical proteins in a series of pancreatic precancerous lesions (pancreatic intraepithelial neoplasia, PanINs) and pancreatic cancers. Cav-1 and FASN expression correlated predominantly with clinical characteristics, such as histologic grade and advanced tumor stage (e.g. high Cav-1 and FASN expression correlated with poor differentiation status) and a significant survival advantage was found in patients with low co-expressing FASN and Cav-1 tumors. Cav-1 and FASN expression was absent in PanIN lesions and the normal ducts and acini. Of note, Cav-1 expression was detected in the fibroblasts of the desmoplastic pancreatic cancer stroma, but not in stromal cells of the normal pancreas. Mechanistically, these data support the notion that these proteins are co-regulated either directly or indirectly by another factor. Importantly, the co-expression of these proteins significantly correlates with clinical features and survival status of pancreatic cancer patients. Thus, Cav-1 and FASN may functionally cooperate in the process of pancreatic tumorigenesis, and as such, may be good candidate prognostic markers and targets for therapeutic intervention.     

Diet and cancer prevention: Dietary compounds,dietary MicroRNAs,and dietary exosomes

Cancer is one of main health public problems worldwide. Several factors are involved in beginning and development of cancer. Genetic and internal/external environmental factors can be as important agents that effect on emerging and development of several cancers. Diet and nutrition may be as one of important factors in prevention or treatment of various cancers. A large number studies indicated that suitable dietary patterns may help to cancer prevention or could inhibit development of tumor in cancer patients. Moreover, a large numbers studies indicated that a variety of dietary compounds such as curcumin, green tea, folat, selenium, and soy isoflavones show a wide range anti‐cancer properties. It has been showed that these compounds via targeting a sequence of cellular and molecular pathways could be used as suitable options for cancer chemoprevention and cancer therapy. Recently, dietary microRNAs and exosomes have been emerged as attractive players in cancer prevention and cancer therapy. These molecules could change behavior of cancer cells via targeting various cellular and molecular pathways involved in cancer pathogenesis. Hence, the utilization of dietary compounds which are associated with powerful molecules such as microRNAs and exosomes and put them in dietary patterns could contribute to prevention or treatment of various cancers. Here, we summarized various studies that assessed effect of dietary patterns on cancer prevention shortly. Moreover, we highlighted the utilization of dietary compounds, dietary microRNAs, and dietary exosomes and their cellular and molecular pathways in cancer chemoprevention.     

Breast and ovarian cancers: a survey and possible roles for the cell surface heparan sulfate proteoglycans

Tumor markers are widely used in pathology not only for diagnostic purposes but also to assess the prognosis and to predict the treatment of the tumor. Because tumor marker levels may change over time, it is important to get a better understanding of the molecular changes during tumor progression. Occurrence of breast and ovarian cancer is high in older women. Common known risk factors of developing these cancers in addition to age are not having children or having children at a later age, the use of hormone replacement therapy, and mutations in certain genes. In addition, women with a history of breast cancer may also develop ovarian cancer. Here, the authors review the different tumor markers of breast and ovarian carcinoma and discuss the expression, mutations, and possible roles of cell surface heparan sulfate proteoglycans during tumorigenesis of these carcinomas. The focus is on two groups of proteoglycans, the transmembrane syndecans and the lipid-anchored glypicans. Both families of proteoglycans have been implicated in cellular responses to growth factors and morphogens, including many now associated with tumor progression.     

胃癌相关miRNA表达的表观遗传学调控机制

胃癌是人类最常见的肿瘤之一,其发病机制尚不完全清楚.微小RNA(microRNA,miRNA)是一组最近发现的长度为22个核苷酸左右的非编码RNA,具有负性调控基因表达的功能.本文对miRNA在胃癌发生中的作用及其表达调控机制进行综述.不断有文献显示,miRNA在多种肿瘤(包括胃癌)的发生过程中发挥着重要作用.作者和其他研究人员发现,miRNA的表达异常(如:miR-421和miR-21的上调或/和miR-31和miR-218的下调等)与胃癌的发生相关,提示miRNA是胃癌发生的重要因素.目前,miRNA表达的分子机制尚未完全明了.最近研究较清楚地显示,miRNA的表达受到DNA甲基化和组蛋白修饰等机制的调控.这说明,胃癌相关miRNA的表达水平受到表观遗传机制的调控。