Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase-type plasminogen activator cascade

Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell motility and plasticity. Although initially regarded as a tumor suppressor, gelsolin expression in certain tumors correlates with poor prognosis and therapy-resistance. In vitro, gelsolin has anti-apoptotic and pro-migratory functions and is critical for invasion of some types of tumor cells. We found that gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues, as examined by immunohistochemistry. Although gelsolin contributes to lamellipodia formation in migrating cells, the mechanisms by which it induces tumor invasion are unclear. Gelsolin’s influence on the invasive activity of colorectal cancer cells was investigated using overexpression and small interfering RNA knockdown. We show that gelsolin is required for invasion of colorectal cancer cells through matrigel. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion-promoting genes in colorectal cancer cells, including the matrix-degrading urokinase-type plasminogen activator (uPA). Conversely, gelsolin knockdown reduces uPA levels, as well as uPA secretion. The enhanced invasiveness of gelsolin-overexpressing cells was attenuated by treatment with function-blocking antibodies to either uPA or its receptor uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. In summary, our data reveals novel functions of gelsolin in colorectal tumor cell invasion through its modulation of the uPA/uPAR cascade, with potentially important roles in colorectal tumor dissemination to metastatic sites

Autophagy modulators : mechanistic aspects and drug delivery systems

Funding: this work was supported by a grant from NMRC-CIRG to CTY. APK was supported by grants from National Medical Research Council of Singapore, NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative to Cancer Science Institute of Singapore, National University of Singapore. R.M. acknowledges financial supports of Kerman University of Medical Sciences.Autophagy modulation is considered to be a promising programmed cell death mechanism to prevent and cure a great number of disorders and diseases. The crucial step in designing an effective therapeutic approach is to understand the correct and accurate causes of diseases and to understand whether autophagy plays a cytoprotective or cytotoxic/cytostatic role in the progression and prevention of disease. This knowledge will help scientists find approaches to manipulate tumor and pathologic cells in order to enhance cellular sensitivity to therapeutics and treat them. Although some conventional therapeutics suffer from poor solubility, bioavailability and controlled release mechanisms, it appears that novel nanoplatforms overcome these obstacles and have led to the design of a theranostic-controlled drug release system with high solubility and active targeting and stimuli-responsive potentials. In this review, we discuss autophagy modulators-related signaling pathways and some of the drug delivery strategies that have been applied to the field of therapeutic application of autophagy modulators. Moreover, we describe how therapeutics will target various steps of the autophagic machinery. Furthermore, nano drug delivery platforms for autophagy targeting and co-delivery of autophagy modulators with chemotherapeutics/siRNA, are also discusse

Targeting autophagy using natural compounds for cancer prevention and therapy

10.1002/cncr.31978CANCER12581228-124

DEAD-box RNA Helicases: the microRNA managers of breast cancer: DOI: 10.14800/rd.846

The roles of non-coding RNAs in cancers, microRNA (miRNA) especially, have sparked interest in the field of RNA research in recent years. The once widely accepted ‘central dogma of genetics’ describing the flow of cellular protein expression is now being challenged following the discovery of non-coding RNA research. miRNAs belong to the family of non-coding RNAs, in which many have been shown to be involved in cancer progression, including breast cancer. Goh et al. have recently summarized comprehensively, the roles of miRNAs in the hallmarks of breast cancer progression. In this research highlight, we provide a brief summary of these miRNA-associated hallmarks in breast cancer progression and also highlight on a family of proteins known as DEAD-box RNA helicases, many of which have been found to be associated with miRNA-associated tumorigenesis. There are an increasing number of studies on DEAD-box RNA helicases in recent years, with different roles being reported in numerous cancer types. DDX20, a member of the DEAD-box RNA helicase family, was most recently identified by our group to be involved in breast cancer progression and metastasis. New data from our group found a possible novel miRNA-processing role of DDX20 in breast cancer. In an ongoing study, we found miRNA miR-222 expression inversely correlates with DDX20, suggesting a possible tumor suppressor role of miR-222 in invasive breast cancers, contrary to previous reports where miR-222 was associated with invasion in breast cancers. Our work thus provides another dimension to the complexity, where miRNAs and DEAD-box RNA helicases play in breast cancers

PI3K/AKT Signaling Tips the Balance of Cytoskeletal Forces for Cancer Progression

10.3390/cancers14071652CANCERS14

HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population

Histone deacetylases (HDACs) are enzymes involved in transcriptional repression. We aimed to examine the significance of HDAC1 and HDAC2 gene expression in the prediction of recurrence and survival in 156 patients with hepatocellular carcinoma (HCC) among a South East Asian population who underwent curative surgical resection in Singapore. We found that HDAC1 and HDAC2 were upregulated in the majority of HCC tissues. The presence of HDAC1 in tumor tissues was correlated with poor tumor differentiation. Notably, HDAC1 expression in adjacent non-tumor hepatic tissues was correlated with the presence of satellite nodules and multiple lesions, suggesting that HDAC1 upregulation within the field of HCC may contribute to tumor spread. Using competing risk regression analysis, we found that increased cancer-specific mortality was significantly associated with HDAC2 expression. Mortality was also increased with high HDAC1 expression. In the liver cancer cell lines, HEP3B, HEPG2, PLC5, and a colorectal cancer cell line, HCT116, the combined knockdown of HDAC1 and HDAC2 increased cell death and reduced cell proliferation as well as colony formation. In contrast, knockdown of either HDAC1 or HDAC2 alone had minimal effects on cell death and proliferation. Taken together, our study suggests that both HDAC1 and HDAC2 exert pro-survival effects in HCC cells, and the combination of isoform-specific HDAC inhibitors against both HDACs may be effective in targeting HCC to reduce mortality

Gelsolin: A new insight of its role on gastric cancer dissemination: DOI: 10.14800/rd.1439

Gastric cancer (GC) is one of the most prevalent cancers worldwide, with more than 700,000 cases of death. Histopathologically, GC can be classified into two main subtypes, the intestinal- and diffuse-type GC. These two subtypes differ not only in histological parameters, but also show distinct profiles of gene alternations. In this research highlight, we provide a summary of gene mutations in both the intestinal- and diffuse-type GC, and also highlight our recent findings on the role gelsolin, an actin-regulating protein, in GC dissemination. We recently found that gelsolin is differentially expressed in intestinal and diffuse type GC, and uncovered its involvement in the HGF/c-Met oncogenic pathway, which is a frequent activated signaling pathway in GC dissemination. Other roles of gelsolin in cancer development have also been discussed, with a focus on its potential link to oncogenic pathways and gene alternations in cancer metastasis. Our work provides a potential link between gelsolin and pro-invasive pathways in GC, and hence suggest a potential avenue for combating GC dissemination and metastasis with consideration of gelsolin status