SPTLC2 drives an EGFR-FAK-HBEGF signaling axis to promote ovarian cancer progression.

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2024-12-07 DOI:10.1038/s41388-024-03249-0

Xingyue Zhai, Ning Shen, Tao Guo, Jianxin Wang, Chunrui Xie, Yukai Cao, Ling Liu, Yumei Yan, Songshu Meng, Sha Du

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引用次数: 0

Abstract

The epidermal growth factor receptor (EGFR) signaling pathway is frequently associated with ovarian cancer (OC) progression. However, inhibition of EGFR signaling in OC patients achieved limited therapeutic effects, highlighting the need to define the mechanism of EGFR deregulation in OC development. Herein we showed that serine palmitoyltransferase long chain base subunit 2 (SPTLC2) acts as a positive regulator in the EGFR signaling pathway in OC. Phenotypically, depletion of SPTLC2 suppressed clonogenic growth and migration of OC cells in vitro and in ovo, as well as metastasis in OC xenograft models, whereas overexpression of SPTLC2 yielded opposite effects. Mechanistically, SPTLC2 drives an EGFR-FAK-HBEGF signaling axis via binding with EGFR. Notably, the serine palmitoyltransferase activity of SPTLC2 is critical for regulation of the EGFR-FAK-HBEGF signaling axis and activity in OC progression. Clinically, high SPTLC2 expression is associated with high-grade serous ovarian cancer and metastasis. Collectively, our findings establish an oncogenic role of SPTLC2 in OC growth and progression though upregulation of EGFR signaling and suggest that SPTLC2 represents a potential therapeutic target in EGFR-driven ovarian cancer patients.

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SPTLC2驱动EGFR-FAK-HBEGF信号轴促进卵巢癌进展。

表皮生长因子受体（EGFR）信号通路通常与卵巢癌（OC）的进展有关。然而，在OC患者中，抑制EGFR信号通路的治疗效果有限，因此需要明确EGFR调控在OC发展中的机制。本研究表明，丝氨酸棕榈酰转移酶长链碱基亚基2 （SPTLC2）在OC的EGFR信号通路中起积极调节作用。从表型上看，SPTLC2的缺失抑制了体外和卵内OC细胞的克隆生长和迁移，以及OC异种移植模型的转移，而SPTLC2的过表达则产生相反的效果。从机制上讲，SPTLC2通过与EGFR结合驱动EGFR- fb - hbegf信号轴。值得注意的是，SPTLC2的丝氨酸棕榈酰转移酶活性对于调节EGFR-FAK-HBEGF信号轴和OC进展中的活性至关重要。临床上，SPTLC2高表达与高级别浆液性卵巢癌及转移有关。总的来说，我们的研究结果通过上调EGFR信号，确立了SPTLC2在卵巢癌生长和进展中的致癌作用，并表明SPTLC2代表了EGFR驱动的卵巢癌患者的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.