Background/Aim: The FOXC2 transcription factor promotes the progression of several cancer types, but has not been investigated in the context of melanoma cells. To study FOXC2's influence on melanoma progression, we generated a FOXC2-deficient murine melanoma cell line and evaluated The Cancer Genome Atlas (TCGA) patient datasets. Materials and Methods: We compared tumor growth kinetics and RNA-seq/qRT-PCR gene expression profiles from wild-type versus FOXC2-deficient murine melanomas. We also performed Kaplan-Meier survival analysis of TCGA data to assess the influence of FOXC2 gene expression on melanoma patients' response to chemotherapy and immunotherapy. Results: FOXC2 promotes melanoma progression and regulates the expression of genes associated with multiple oncogenic pathways, including the oxidative stress response, xenobiotic metabolism, and interferon responsiveness. FOXC2 expression in melanoma correlates negatively with patient response to chemotherapy and immunotherapy. Conclusion: FOXC2 drives a tumor-promoting gene expression program in melanoma and is a prognostic indicator of patient response to multiple cancer therapies. Melanoma, a highly aggressive form of cancer arising from pigment-producing melanocytes, is responsible for the majority of skin cancer-related mortality, accounting for~6 0,000 annual deaths worldwide (1). Importantly, the incidence of melanoma has risen substantially over the last 40 years (2), a trend that is expected to continue to at least 2031 (3). Although surgical removal of primary lesions is typically successful in the treatment of early-stage disease, many melanoma patients are not diagnosed until later stages of metastatic disease in which surgery is either not possible or largely ineffective. Unfortunately, malignant melanoma is highly resistant to radiation and chemotherapy, and the only FDA-approved chemotherapeutic for the treatment of melanoma, dacarbazine (DTIC), has a minimal impact on patient survival (4). While advances in targeted therapy and immunotherapy have improved the prognosis for melanoma in recent years, there are still patients who do not respond to these regimens, and relapse of therapy-resistant tumors remains an ongoing challenge in many patients who do achieve clinical benefit (5, 6). Therefore, in order to improve the clinical outcome of melanoma patients going forward, it is necessary to gain additional insight into factors that promote melanoma progression and resistance to these therapeutic modalities. FOXC2 is a member of the forkhead box family of transcription factors that control a variety of cellular processes in embryonic and adult tissues. In addition to its normal regulation of development, growth, and metabolism in various tissue types, FOXC2 has recently emerged as a driver of several hallmarks of cancer progression as well. Within vascular endothelial cells, FOXC2 promotes expression of multiple genes that enhance angiogenesis (7-9). FOXC2 can also become overexpressed or dysregulated in tumor cells themselves, where it is asso...
FOXC2, a member of the forkhead box family of transcription factors, is an emerging oncogene that has been linked to several hallmarks of cancer progression. Among its many oncogenic functions is the promotion of drug resistance, with evidence supporting roles for FOXC2 in escape from broad classes of chemotherapeutics across an array of cancer types. In this Mini-Review, we highlight the current understanding of the mechanisms by which FOXC2 drives cancer chemoresistance, including its roles in the promotion of epithelial-mesenchymal transition, induction of multidrug transporters, activation of the oxidative stress response, and deregulation of cell survival signaling pathways. We discuss the clinical implications of these findings, including strategies for modulating FOXC2-associated chemoresistance in cancer. Particular attention is given to ways in which FOXC2 and its downstream gene products and pathways can be targeted to restore chemosensitivity in cancer cells. In addition, the utility of FOXC2 expression as a predictor of patient response to chemotherapy is also highlighted, with emphasis on the value of FOXC2 as a novel biomarker that can be used to guide therapeutic choice towards regimens most likely to achieve clinical benefit during frontline therapy.
Over the past decade, interest in nanoparticles as a therapeutic tool has skyrocketed as technological advances have made them cheaper and easier to use. Nanoparticles in themselves act as vehicles for proteins, enzymes, drugs, etc. and carry them throughout a biological system to a specific target. However, with proteins being simply bound to the nanoparticles, problems arise with these proteins being susceptible to denaturation. Encapsulation of proteins within nanoparticles provides an advantage over simple binding and gives many benefits through its protection of the proteins. Through encapsulation, proteins are protected by, in this case, a silica shell. This shell prevents the protein from denaturing from heat, acidity, or metabolism. All the while, the drug or enzyme that is encapsulated should still maintain its function and interact with a target site because the silica shell contains small pores that allow for such reactions to proceed.To establish and refine the encapsulation protocol in the context of our laboratory, we attempted a water‐in‐oil reverse microemulsion process on myoglobin, green fluorescent protein (GFP), and chymotrypsin. Since silica nanoparticles have been shown to be biocompatible in humans and have a great deal of biological significance, we chose to use a silica‐based approach for nanoparticle synthesis. The silica nanoparticles that we synthesized were mesoporous, which allowed the nanoparticles to be biocompatible due to their low hemolytic activity. Due to such biocompatibility, these nanoparticles can be used for things such as drug delivery, biosensors, imaging, and more.Results showed that encapsulation was successful through spectrophotometry absorbance and fluorescent microscopy measurements for myoglobin and GFP encapsulation, respectively. The catalytic function of the encapsulated proteins was then shown through absorbance experiments run on encapsulated chymotrypsin. Current work is focusing on using these techniques for the encapsulation of several clinically relevant protein targets of similar size to the examples presented here.Support or Funding InformationNational Science Foundation Award #1626602This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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