Serine hydroxymethyl transferase 1 stimulates pro-oncogenic cytokine expression through sialic acid to promote ovarian cancer tumor growth and progression.
Serine hydroxymethyl transferase 1 stimulates pro-oncogenic cytokine expression through sialic acid to promote ovarian cancer tumor growth and progression.
复制标题
DOI：
10.1038/onc.2017.37
复制
发表时间：
2017-07-13
期刊：
影响因子：
8
通讯作者：
Wajapeyee N
中科院分区：
文献类型：
--
作者：
Gupta R;Yang Q;Dogra SK;Wajapeyee N
高级别浆液性(HGS)卵巢癌占所有卵巢癌相关死亡的90%。然而，推动HGS卵巢癌肿瘤生长的因素尚未完全阐明。特别是，对卵巢癌肿瘤生长的代谢需求还没有进行全面的分析。通过分析HGS卵巢癌患者肿瘤基因组图谱的mRNA表达数据，我们观察到HGS卵巢癌组织中叶酸代谢途径的六种酶与正常卵巢组织相比过表达。利用短发夹状RNA(ShRNAs)系统地敲除了所有6个基因，并进行了后续的功能研究，结果表明，丝氨酸羟甲基转移酶1(SHMT1)在小鼠卵巢癌的生长、细胞迁移和肿瘤形成中是必需的。SHMT1启动子分析确定了转录因子Wilms Tumor 1(WT1)的结合部位，WT1基因敲除导致卵巢癌细胞SHMT1转录降低。无偏见的大规模代谢组学分析和全转录范围的mRNA表达谱发现，包括唾液酸N-乙酰神经氨酸(Neu5Ac)在内的氨基糖和核苷酸代谢途径的几种代谢物水平降低，以及致癌细胞因子IL-6和IL-8的下调是SHMT1缺失的意外结果。过表达IL-6或IL-8可部分挽救SHMT1缺失诱导的肿瘤生长抑制和迁移。加入Neu5Ac刺激IL-6和IL-8的表达，并挽救表达SHMT1 shRNAs的卵巢癌细胞的生长和迁移表型。与Neu5Ac促进卵巢肿瘤的作用一致，Neu5Ac靶向糖类药物P-3Fax-Neu5Ac治疗阻止了卵巢癌的生长和迁移。综上所述，这些结果表明，SHMT1通过调节唾液酸Neu5Ac来促进卵巢癌肿瘤的生长和迁移，从而控制致瘤性炎症细胞因子的表达。因此，靶向SHMT1和Neu5Ac代表了有效治疗HGS卵巢癌的精确治疗机会。
High-grade serous (HGS) ovarian cancer accounts for 90% of all ovarian cancer-related deaths. However, factors that drive HGS ovarian cancer tumor growth have not been fully elucidated. In particular, comprehensive analysis of the metabolic requirements of ovarian cancer tumor growth has not been performed. By analyzing The Cancer Genome Atlas mRNA expression data for HGS ovarian cancer patient samples, we observed that six enzymes of the folic acid metabolic pathway were overexpressed in HGS ovarian cancer samples compared with normal ovary samples. Systematic knockdown of all six genes using short hairpin RNAs (shRNAs) and follow-up functional studies demonstrated that serine hydroxymethyl transferase 1 (SHMT1) was necessary for ovarian cancer tumor growth and cell migration in culture and tumor formation in mice. SHMT1 promoter analysis identified transcription factor Wilms tumor 1 (WT1) binding sites, and WT1 knockdown resulted in reduced SHMT1 transcription in ovarian cancer cells. Unbiased large-scale metabolomic analysis and transcriptome-wide mRNA expression profiling identified reduced levels of several metabolites of the amino sugar and nucleotide sugar metabolic pathways, including sialic acid N-acetylneuraminic acid (Neu5Ac), and downregulation of pro-oncogenic cytokines interleukin-6 and 8 (IL-6 and IL-8) as unexpected outcomes of SHMT1 loss. Overexpression of either IL-6 or IL-8 partially rescued SHMT1 loss-induced tumor growth inhibition and migration. Supplementation of culture medium with Neu5Ac stimulated expression of IL-6 and IL-8 and rescued the tumor growth and migratory phenotypes of ovarian cancer cells expressing SHMT1 shRNAs. In agreement with the ovarian tumor-promoting role of Neu5Ac, treatment with Neu5Ac-targeting glycomimetic P-3Fax-Neu5Ac blocked ovarian cancer growth and migration. Collectively, these results demonstrate that SHMT1 controls the expression of pro-oncogenic inflammatory cytokines by regulating sialic acid Neu5Ac to promote ovarian cancer tumor growth and migration. Thus, targeting of SHMT1 and Neu5Ac represents a precision therapy opportunity for effective HGS ovarian cancer treatment.
登录
查看更多内容
影响因子：
2.8
作者：
Succi, Maysa;de Castro, Tialfi Bergamin;Goloni-Bertollo, Eny Maria
通讯作者：
Goloni-Bertollo, Eny Maria
STAT3信号通路诱导的BDNF自分泌活性导致TrkB延长激活并促进人非小细胞肺癌增殖
影响因子：
4.6
作者：
Chen B;Liang Y;He Z;An Y;Zhao W;Wu J
通讯作者：
Wu J
影响因子：
64.8
作者：
Possemato, Richard;Marks, Kevin M.;Shaul, Yoav D.;Pacold, Michael E.;Kim, Dohoon;Birsoy, Kivanc;Sethumadhavan, Shalini;Woo, Hin-Koon;Jang, Hyun G.;Jha, Abhishek K.;Chen, Walter W.;Barrett, Francesca G.;Stransky, Nicolas;Tsun, Zhi-Yang;Cowley, Glenn S.;Barretina, Jordi;Kalaany, Nada Y.;Hsu, Peggy P.;Ottina, Kathleen;Chan, Albert M.;Yuan, Bingbing;Garraway, Levi A.;Root, David E.;Mino-Kenudson, Mari;Brachtel, Elena F.;Driggers, Edward M.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
9
作者：
通讯作者：
--
影响因子：
15.9
作者：
Gao, Sizhi Paul;Mark, Kevin G.;Bromberg, Jacqueline F.
通讯作者：
Bromberg, Jacqueline F.