PMC:5337621 / 2215-6729 JSONTXT

{"project":"2_test","denotations":[{"id":"28218735-25589897-79088286","span":{"begin":127,"end":128},"obj":"25589897"},{"id":"28218735-20425077-79088287","span":{"begin":382,"end":383},"obj":"20425077"},{"id":"28218735-26221076-79088288","span":{"begin":713,"end":714},"obj":"26221076"},{"id":"28218735-19278896-79088289","span":{"begin":716,"end":717},"obj":"19278896"},{"id":"28218735-23516109-79088290","span":{"begin":811,"end":812},"obj":"23516109"},{"id":"28218735-16581905-79088291","span":{"begin":1043,"end":1044},"obj":"16581905"},{"id":"28218735-17259342-79088292","span":{"begin":1145,"end":1146},"obj":"17259342"},{"id":"28218735-26782714-79088293","span":{"begin":1252,"end":1253},"obj":"26782714"},{"id":"28218735-15289843-79088294","span":{"begin":1773,"end":1774},"obj":"15289843"},{"id":"28218735-24240108-79088295","span":{"begin":1862,"end":1864},"obj":"24240108"},{"id":"28218735-14734480-79088296","span":{"begin":2234,"end":2236},"obj":"14734480"},{"id":"28218735-24793696-79088297","span":{"begin":2374,"end":2376},"obj":"24793696"},{"id":"28218735-24531137-79088298","span":{"begin":2882,"end":2884},"obj":"24531137"},{"id":"28218735-24531137-79088299","span":{"begin":3035,"end":3037},"obj":"24531137"},{"id":"28218735-19252483-79088300","span":{"begin":3039,"end":3041},"obj":"19252483"},{"id":"28218735-24487129-79088301","span":{"begin":3043,"end":3045},"obj":"24487129"},{"id":"28218735-21715311-79088302","span":{"begin":3206,"end":3208},"obj":"21715311"},{"id":"28218735-16185509-79088303","span":{"begin":3227,"end":3229},"obj":"16185509"},{"id":"28218735-23146905-79088304","span":{"begin":3243,"end":3245},"obj":"23146905"},{"id":"28218735-23869764-79088305","span":{"begin":3265,"end":3267},"obj":"23869764"},{"id":"28218735-16731740-79088306","span":{"begin":3529,"end":3531},"obj":"16731740"},{"id":"28218735-19336448-79088307","span":{"begin":3680,"end":3682},"obj":"19336448"},{"id":"28218735-23938875-79088308","span":{"begin":3802,"end":3804},"obj":"23938875"},{"id":"28218735-25288231-79088309","span":{"begin":3988,"end":3990},"obj":"25288231"},{"id":"28218735-22331265-79088310","span":{"begin":4024,"end":4026},"obj":"22331265"}],"text":"Introduction\nGastric cancer is one of the most common cancers with high incidence of disease-related deaths and poor prognosis.1 Currently, surgical resection and chemotherapy are the most effective treatments. However, patients with locally advanced disease respond poorly to chemotherapeutic modalities, reflecting an inherent refractive mechanism against drug-induced cell death.2 Several previous reports have attempted to explore the molecular markers that drive drug resistance. These proposed markers and signatures, including PI3K/Akt, NFκB, inhibitors of apoptosis (IAPs) and Bcl-2 family proteins, are highly expressed in gastric cancer and associated with resistance to chemotherapy-induced cell death.3, 4\nAurora kinases were first identified in Drosophila as key players in chromosomal segregation.5 Subsequently, orthologues were also discovered in humans and implicated in the control of distinct and unrelated aspects of mitosis. Human Aurora kinase A (AURKA) is essential for centrosome duplication, maturation and separation.6 AURKA is a potent oncogene that has the capacity to transform certain cell lines when overexpressed.7 Recent evidence demonstrated that AURKA could regulate c-Myc expression through cooperating with hnRNP K.8 AURKA overexpression is also a hallmark of many cancers and can enhance chromosomal instability through centrosome amplification. The human AURKA gene maps to chromosome region 20q13.2, which is frequently amplified in different malignancies, including gastric cancer. A previous study showed that AURKA overexpression and amplification are involved in differentiated-type gastric carcinogenesis and the development of aneuploidy, suggesting that it might contribute to the initiation and progression of gastric cancer.9 AURKA has also been implicated in taxane and microtubule destabilizing drug resistance;10 however, its role in gastric cancer, especially in resistance to DNA-damaging therapeutic agents remains undefined. Importantly, a previous study using comparative genomic hybridization array found that AURKA overexpression in high-risk primary gastric cancer tissues is associated with dysregulated expression of DNA damage response genes, which also include Survivin.11\nSurvivin is the smallest member of human IAPs and has two critical but not yet fully elucidated roles in cell proliferation and survival.12 First, Survivin is highly expressed in many human malignancies and can restrict programmed cell death by inhibiting the function of executioner caspases and procaspases. Secondly, Survivin is also part of the chromosomal passenger complex and responsible for recruiting chromosomal passenger complex to mitotic chromosome, thus having a crucial role in genome stability. In addition to these widely studied functions, Survivin also has an important but less well studied role in microtubule stabilization.13 Survivin is an oncofetal protein with elevated expression in stem and cancer cells, while expressed at low level in normal adult differentiated cells.13, 14, 15 Survivin has been reported to be overexpressed in both solid tumors and hematological malignancies and its overexpression linked to drug resistance in leukemia,16, 17 breast cancer,18 neuroblastoma19 and ovarian cancer.20 Survivin expression has both positive and negative effects on clinical prognosis depending on its location. Nuclear Survivin has been associated with a better prognosis, whereas cytoplasmic Survivin is associated with in some cancer types poor clinical outcome.21 In gastric cancer, the five-year survival rate of patients with positive Survivin expression is significantly lower than Survivin-negative patients.22 Survivin protein undergoes post-translational modifications, including acetylation, phosphorylation and ubiquitylation,23 and these processes modulate Survivin activity.\nAlthough there is strong evidence that AURKA and Survivin are simultaneously co-overexpressed in various malignancies, including breast24 and chronic lymphocytic leukemia,25 relatively little is known about their expression, regulation and function in gastric cancer. In this study, we addressed this question and found that AURKA and Survivin cooperated in gastric cancer development and had a decisive role in resistance to DNA-damaging agents and poor cancer prognosis. Moreover, we revealed that AURKA stabilized Survivin protein by suppressing its protein degradation through negatively regulating Forkhead box protein P1 (FOXP1)-mediated FBXL7 expression."}