Chondroitin polymerizing factor predicts a poor prognosis and promotes breast cancer progression via the upstream TGF-β1/SMAD3 and JNK axis activation
Chondroitin polymerizing factor predicts a poor prognosis and promotes breast cancer progression via the upstream TGF-β1/SMAD3 and JNK axis activation
复制标题
软骨素聚合因子通过上游 TGF-β1/SMAD3 和 JNK 轴激活预测不良预后并促进乳腺癌进展
DOI：
10.1007/s12079-022-00684-0
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发表时间：
2022-08-30
影响因子：
4.1
通讯作者：
Zhang，Jun
中科院分区：
文献类型：
--
作者：
Pan，Qiang-Feng;Ouyang，Wei-Wei;Zhang，Jun
肿瘤微环境（TME）中聚糖的异常组成有助于肿瘤的进展和转移。软骨素聚合因子 (CHPF) 是一种糖基转移酶，可催化硫酸软骨素 (CS) 的生物合成。它还与转化生长因子-β1 (TGF-β1) 表达相关，转化生长因子-β1 是癌细胞与 TME 相互作用的关键介质。在本研究中，我们研究了CHPF表达与乳腺癌（BRCA）临床病理特征的关联，以及CHPF对BRCA细胞的致癌作用和潜在机制。我们发现人BRCA组织中CHPF表达显着升高，且与TGF-β表达呈正相关（r = 0.7125）。 CHPF的高表达预示着预后不良，并且与肿瘤质量、淋巴结转移、临床分期和HER-2阴性表达呈正相关。机制研究表明，其在体外通过TGF-β1诱导的SMAD3和JNK激活促进BRCA细胞增殖、迁移和侵袭，JNK（SP600125）或SMAD3（SIS3）抑制剂可以消除CHPF对源自三阴性乳腺癌（TNBC）的MDA-MB-231细胞的细胞增殖、迁移和侵袭的促进作用。总的来说，我们的发现表明 CHPF 可能作为一种癌基因发挥作用，并且在人类 BRCA 组织中高度表达。药物阻断 JNK 或 SMAD3 信号上游可能为 CHPF 异常高表达的难治性 TNBC 患者提供新的治疗靶点。
Aberrant composition of glycans in the tumor microenvironment (TME) contributes to tumor progression and metastasis. Chondroitin polymerizing factor (CHPF) is a glycosyltransferase that catalyzes the biosynthesis of chondroitin sulfate (CS). It is also correlated to transforming growth factor-β1 (TGF-β1) expression, a crucial mediator in the interaction of cancer cells with TME. In this study, we investigated the association of CHPF expression with the clinicopathological features of breast cancer (BRCA), as well the oncogenic effect and the underling mechanisms of CHPF upon BRCA cells. We found that CHPF expression is significantly increased in human BRCA tissues, and it is positively associated with TGF-β expression (r = 0.7125). The high-expression of CHPF predicts a poor prognosis and is positively correlated with tumor mass, lymph node metastasis, clinical staging and HER-2 negative-expression. The mechanistic study revealed that it promotes BRCA cell proliferation, migration and invasion through TGF-β1-induced SMAD3 and JNK activation in vitro, JNK (SP600125) or SMAD3 (SIS3) inhibitor can remove the promotion of CHPF upon cell proliferation, migration and invasion in MDA-MB-231 cells, which is derived from triple-negative breast cancer (TNBC). Collectively, our finding suggested CHPF may function as an oncogene and is highly expressed in human BRCA tissues. Pharmacological blockade of the upstream of JNK or SMAD3 signaling may provide a novel therapeutic target for refractory TNBC patients with CHPF abnormal high-expression.