The analysis of microRNA-34 family expression in human cancer studies comparing cancer tissues with corresponding pericarcinous tissues

Recently many studies have focused on the microRNA-34 (miR-34) family expression in various cancers; nevertheless, the controversial results of these studies still exist in identifying miR-34 members as new biomarkers of cancers. Therefore, we carried out this comprehensive meta-analysis of published studies that compared the miR-34 family expression profiles between cancer tissues and paired neighboring noncancerous tissues to systemically evaluate the findings globally and address the inconsistencies of pertinent literatures. The data included in this article were collected from Embase, PubMed and Web of Science up to December 2013. To overcome the difficulties that many raw data were unavailable and study methods were different, a vote-counting strategy was adopted to identify consistent markers in our analysis. Ultimately, a total of 23 cancers were reported in the 61 eligible studies, of which 46 studies provided fold-change value information. In the consistently reported cancer types, non-small cell lung cancer (NSCLC), glioma and nasopharyngeal carcinoma (NPC) ranked at the top with down-regulated feature. Cervical neoplasm was consistently reported to be over-expressed in the panel of each member of miR-34s. Subgroup analysis of miR-34 family expression demonstrated that colorectal cancer (CRC), gastric cancer (GC), hepatocellular carcinoma (HCC) and prostate cancer (PCa) were most frequently reported with inconsistent regulations. Our meta-analysis showed that miR-34 family members could be expected to become potential diagnostic and prognostic biomarkers in some types of human cancers. Further well-designed and larger sample studies are surely warranted to identify the role of the miR-34 family in the occurrence and development of tumors.     

Sialosignaling: Sialyltransferases as engines of self-fueling loops in cancer progression

Background

Glycosylation is increasingly recognized as one of the most relevant postranslational modifications. Sialic acids are negatively charged sugars which frequently terminate the carbohydrate chains of glycoproteins and glycolipids. The addition of sialic acids is mediated by sialyltransferases, a family of glycosyltransferases with a crucial role in cancer progression.

Scope of the review

To describe the phenotypic and clinical implications of altered expression of sialyltransferases and of their cognate sialylated structures in cancer. To propose a unifying model of the role of sialyltransferases and sialylated structures on cancer progression.

Major conclusions

We first discuss the biosynthesis and the role played by the major cancer-associated sialylated structures, including Thomsen–Friedenreich-associated antigens, sialyl Lewis antigens, α2,6-sialylated lactosamine, polysialic acid and gangliosides. Then, we show that altered sialyltransferase expression in cancer, consequence of genetic and epigenetic alterations, generates a flow of information toward the membrane through the biosynthesis of aberrantly sialylated molecules (inside-out signaling). In turn, the presence of aberrantly sialylated structures on cell membrane receptors generates a flow of information toward the nucleus, which can exacerbate the neoplastic phenotype (outside-in signaling). We provide examples of self-fueling loops generated by these flows of information.

General significance

Sialyltransferases have a wide impact on the biology of cancer and can be the target of innovative therapies. Our unified view provides a conceptual framework to understand the impact of altered glycosylation in cancer.     

Frizzled7 as an emerging target for cancer therapy

Wnt proteins are secreted glycoproteins that bind to the N-terminal extra-cellular cysteine-rich domain of the Frizzled (Fzd) receptor family. The Fzd receptors can respond to Wnt proteins in the presence of Wnt co-receptors to activate the canonical and non-canonical Wnt pathways. Recent studies indicated that, among the Fzd family, Fzd7 is the Wnt receptor most commonly upregulated in a variety of cancers including colorectal cancer, hepatocellular carcinoma and triple negative breast cancer. Fzd7 plays an important role in stem cell biology and cancer development and progression. In addition, it has been demonstrated that siRNA knockdown of Fzd7, the anti-Fzd7 antibody or the extracellular peptide of Fzd7 (soluble Fzd7 peptide) displayed anti-cancer activity in vitro and in vivo mainly due to the inhibition of the canonical Wnt signaling pathway. Furthermore, pharmacological inhibition of Fzd7 by small interfering peptides or a small molecule inhibitor suppressed β-catenin-dependent tumor cell growth. Therefore, targeted inhibition of Fzd7 represents a rational and promising new approach for cancer therapy.     

Reformation in chimeric antigen receptor based cancer immunotherapy: Redirecting natural killer cell

Natural killer (NK) cells are an important subset of lymphocytes which play a critical role in host immunity against cancers. With MHC-independent recognition, short lifespan and potent cytotoxicity, NK cells make a promising candidate for chimeric antigen receptor (CAR)-engineered cancer immunotherapy. Due to innate biological properties of NK cells, CAR-NK may outperform CAR-T therapy in terms of less side effects and more universal access, which may become a great reformation in CAR-based cancer immunotherapy. The CARs used in peripheral blood (PB) NK cells as well as NK cell line like NK-92 are the most important outfits defining antigenic specificity. The constructs of CARs used in NK cells from different sources vary, which all undergo generational optimization. The anti-tumor effects of CAR-NK have been validated in numerous preclinical trials for cancers, including hematologic malignancies and many solid tumors, which provide evidence for potential clinical application of CAR-NK. Additionally, this review concludes the challenges faced in the application of CAR-NK. Although CAR-NK is considered as one of the most possible “off-the-shelf” products, the improvement for the efficiency of expansion and transduction as well as the solution for underlying safety issues is still needed. Possible coping strategies for challenges and upgrades in techniques are also highlighted for future development in CAR-NK cancer immunotherapy.     

Mutation and expression analysis of the IDH1, IDH2, DNMT3A, and MYD88 genes in colorectal cancer

Colorectal cancer (CRC) is one of the leading causes of death around the world. Its genetic mechanism was intensively investigated in the past decades with findings of a number of canonical oncogenes and tumor-suppressor genes such as APC, KRAS, and TP53. Recent genome-wide association and sequencing studies have identified a series of promising oncogenes including IDH1, IDH2, DNMT3A, and MYD88 in hematologic malignancies. However, whether these genes are involved in CRC remains unknown. In this study, we screened the hotspot mutations of these four genes in 305 CRC samples from Han Chinese by direct sequencing. mRNA expression levels of these genes were quantified by quantitative real-time PCR (RT-qPCR) in paired cancerous and paracancerous tissues. Association analyses between mRNA expression levels and different cancerous stages were performed. Except for one patient harboring IDH1 mutation p.I99M, we identified no previously reported hotspot mutations in colorectal cancer tissues. mRNA expression levels of IDH1, DNMT3A, and MYD88, but not IDH2, were significantly decreased in the cancerous tissues comparing with the paired paracancerous normal tissues. Taken together, the hotspot mutations of IDH1, IDH2, DNMT3A, and MYD88 gene were absent in CRC. Aberrant mRNA expression of IDH1, DNMT3A, and MYD88 gene might be actively involved in the development of CRC.