// Shivakumar Keerthikumar 1,* , Lahiru Gangoda 1,* , Michael Liem 1 , Pamali Fonseka 1 , Ishara Atukorala 1 , Cemil Ozcitti 1 , Adam Mechler 2 , Christopher G. Adda 1 , Ching-Seng Ang 3 and Suresh Mathivanan 1 1 Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia 2 Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia 3 Bio21 Institute, University of Melbourne, Victoria, Australia * These authors have contributed equally to this work Correspondence to: Suresh Mathivanan, email: // Keywords : exosomes, ectosomes, proteogenomics, extracellular vesicles, integrated OMICs analysis Received : January 27, 2015 Accepted : March 18, 2015 Published : April 12, 2015 Abstract Extracellular vesicles (EVs) include the exosomes (30-100 nm) that are produced through the endocytic pathway via the multivesicular bodies and the ectosomes (100-1000 nm) that are released through the budding of the plasma membrane. Despite the differences in the mode of biogenesis and size, reliable markers that can distinguish between exosomes and ectosomes are non-existent. Moreover, the precise functional differences between exosomes and ectosomes remains poorly characterised. Here, using label-free quantitative proteomics, we highlight proteins that could be exploited as markers to discriminate between exosomes and ectosomes. For the first time, a global proteogenomics analysis unveiled the secretion of mutant proteins that are implicated in cancer progression through tumor-derived EVs. Follow up integrated bioinformatics analysis highlighted the enrichment of oncogenic cargo in exosomes and ectosomes. Interestingly, exosomes induced significant cell proliferation and migration in recipient cells compared to ectosomes confirming the oncogenic nature of exosomes. These findings ascertain that cancer cells facilitate oncogenesis by the secretion of mutant and oncoproteins into the tumor microenvironment via exosomes and ectosomes. The integrative proteogenomics approach utilized in this study has the potential to identify disease biomarker candidates which can be later assayed in liquid biopsies obtained from cancer patients.

/pdf/proteogenomic-analysis-reveals-exosomes-are-more-oncogenic-4pjc5tiim1.pdf

Proteogenomic analysis reveals exosomes are more oncogenic than ectosomes

The resistance of cancer cells to chemotherapeutic agents represents the main problem in cancer treatment. Despite intensive research, mechanisms of resistance have not yet been fully elucidated. Six1 signaling has an important role in the expansion of progenitor cell populations during early embryogenesis. Six1 gene overexpression has been strongly associated with aggressiveness, invasiveness, and poor prognosis of different cancers. In this study, we investigated the role of Six1 signaling in resistance of MCF-7 breast cancer cells to taxanes. We first established in vitro paclitaxel-resistant MCF-7 breast cancer cells. Morphological modifications in paclitaxel-resistant cells were examined via light microscopic images and fluorescence-activated cell sorting analysis. Applying quantitative real-time polymerase chain reaction, we measured Six1, B-cell lymphoma/leukemia(BCL-2), BAX, and P53 mRNA expression levels in both non-resistant and resistant cells. Resistant cells were developed from the parent MCF-7 cells by applying increasing concentrations of paclitaxel up to 64 nM. The inhibitory concentration 50% value in resistant cells increased from 3.5 ± 0.03 to 511 ± 10.22 nM (p = 0.015). In paclitaxel-resistant cells, there was a significant increase in Six1 and BCL-2 mRNA levels (p = 0.0007) with a marked decrease in pro-apoptotic Bax mRNA expression level (p = 0.03); however, there was no significant change in P53 expression (p = 0.025). Our results suggest that identifying cancer patients with high Six1 expression and then inhibition of Six1 signaling can improve the efficiency of chemotherapeutic agents in the induction of apoptosis.

/pdf/the-role-of-six1-signaling-in-paclitaxel-dependent-apoptosis-gvee1gdgur.pdf

The role of Six1 signaling in paclitaxel-dependent apoptosis in MCF-7 cell line

Proteomic methodologies for identification and analysis of biomarkers have gained more attention during recent years and have evolved rapidly. Identification and detection of disease biomarkers are important to foresee outbreaks of certain diseases thereby avoiding surgery and other invasive and expensive medical treatments for patients. Thus, more research into discovering new biomarkers and new methods for faster and more accurate detection is needed. It is often difficult to detect and measure biomarkers because of their low concentrations and the complexity of their respective matrices. Therefore it is hard to find and validate methods for accurate screening methods suitable for clinical use. The most recent developments during the last three years and also some historical considerations of proteomic methodologies for identification and validation of disease biomarkers are presented in this review.

Recent developments in proteomic methods and disease biomarkers

The sine oculis (SIX) family of transcription factors are key regulators of developmental processes during embryogenesis. Members of this family control gene expression to promote self-renewal of progenitor cell populations and govern mechanisms of cell differentiation. When the function of SIX genes becomes disrupted, distinct congenital defects develops both in animal models and humans. In addition to the embryonic setting, members of the SIX family have been found to be critical regulators of tumorigenesis, promoting cell proliferation, epithelial-to-mesenchymal transition, and metastasis. Research in both the fields of developmental biology and cancer research have provided an extensive understanding of SIX family transcription factor functions. Here we review recent progress in elucidating the role of SIX family genes in congenital disease as well as in the promotion of cancer. Common themes arise when comparing SIX transcription factor function during embryonic and cancer development. We highlight the complementary nature of these two fields and how knowledge in one area can open new aspects of experimentation in the other.

/pdf/the-six-family-of-transcription-factors-common-themes-3ewxh6adx6.pdf

The SIX Family of Transcription Factors: Common Themes Integrating Developmental and Cancer Biology.

Sineoculis homeobox homolog 1 protein is associated with breast cancer progression and survival outcome

Sineoculis homeobox homolog 1 protein overexpression as an independent biomarker for pancreatic ductal adenocarcinoma.

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Sineoculis homeobox homolog 1 protein overexpression as an independent biomarker for pancreatic ductal adenocarcinoma.