Proteomic profiling reveals CEACAM6 function in driving gallbladder cancer aggressiveness through integrin receptor, PRKCD and AKT/ERK signaling.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-28 DOI:10.1038/s41419-024-07171-x
Raisatun Nisa Sugiyanto, Carmen Metzger, Aslihan Inal, Felicia Truckenmueller, Kira Gür, Eva Eiteneuer, Thorben Huth, Angelika Fraas, Ivonne Heinze, Joanna Kirkpatrick, Carsten Sticht, Thomas Albrecht, Benjamin Goeppert, Tanja Poth, Stefan Pusch, Arianeb Mehrabi, Peter Schirmacher, Junfang Ji, Alessandro Ori, Stephanie Roessler
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Abstract

Gallbladder cancer (GBC) presents as an aggressive malignancy with poor patient outcome. Like other epithelial cancers, the mechanisms of GBC cancer progression remain vague and efforts in finding targeted therapies fall below expectations. This study combined proteomic analysis of formalin-fixed paraffin-embedded (FFPE) GBC samples, functional and molecular characterization of potential oncogenes and identification of potential therapeutic strategies for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the significantly most upregulated proteins in GBC. CEACAM6 overexpression has been observed in other cancer entities but the molecular function remains unclear. Our functional analyses in vitro and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer progression and metastasis by decreasing cell adhesion and promoting migration and invasion of GBC cells. Conversely, CEACAM6 knockdown abolished GBC aggressiveness by increasing cell adhesion while reducing cell migration, cell proliferation, and colony formation. BirA-BioID followed by mass-spectrometry revealed Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 supporting GBC cell migration. ERK and AKT signaling and their downstream target genes were regulated by CEACAM6 and thus the treatment with AKT inhibitor capivasertib or ERK inhibitor ulixertinib mitigated the CEACAM6-induced migration. These findings demonstrate that CEACAM6 is crucially involved in gallbladder cancer progression by promoting migration and inhibiting cell adhesion through ERK and AKT signaling providing specific options for treatment of CEACAM6-positive cancers.

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蛋白质组分析揭示了 CEACAM6 在通过整合素受体、PRKCD 和 AKT/ERK 信号转导驱动胆囊癌侵袭性方面的功能。
胆囊癌(GBC)是一种侵袭性恶性肿瘤,患者预后较差。与其他上皮癌一样,GBC 癌症进展的机制仍然模糊不清,寻找靶向疗法的努力也不尽如人意。这项研究结合了福尔马林固定石蜡包埋(FFPE)GBC样本的蛋白质组分析、潜在癌基因的功能和分子特征鉴定以及GBC潜在治疗策略的确定。我们发现癌胚抗原相关细胞粘附分子6(CEACAM6)是GBC中明显上调最多的蛋白质之一。在其他癌症实体中也观察到 CEACAM6 过表达,但其分子功能仍不清楚。我们在体外和体内小鼠模型中进行的功能分析显示,CEACAM6 通过降低细胞粘附性、促进 GBC 细胞的迁移和侵袭,支持癌症进展和转移的初始步骤。相反,敲除 CEACAM6 会增加细胞粘附性,同时减少细胞迁移、细胞增殖和集落形成,从而削弱 GBC 的侵袭性。BirA-BioID 随后的质谱分析显示,Integrin Beta-1 (ITGB1) 和 Protein Kinase C Delta (PRKCD) 是 CEACAM6 支持 GBC 细胞迁移的直接分子和功能伙伴。ERK和AKT信号及其下游靶基因受CEACAM6调控,因此用AKT抑制剂capivasertib或ERK抑制剂ulixertinib治疗可减轻CEACAM6诱导的迁移。这些研究结果表明,CEACAM6通过ERK和AKT信号转导促进迁移和抑制细胞粘附,在胆囊癌的进展过程中起着至关重要的作用,这为治疗CEACAM6阳性癌症提供了特异性选择。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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