胱硫醚γ-裂解酶的失调促进前列腺癌的进展和转移。,EMBO Reports

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胱硫醚γ-裂解酶的失调促进前列腺癌的进展和转移。
EMBO Reports ( IF 6.5 ) Pub Date : 2019-08-29 , DOI: 10.15252/embr.201845986
Yi-Hsiang Wang,Jo-Ting Huang,Wen-Ling Chen,Rong-Hsuan Wang,Ming-Chien Kao,Yan-Ru Pan,Shih-Hsuan Chan,Kuo-Wang Tsai,Hsing-Jien Kung,Kai-Ti Lin,Lu-Hai Wang

硫化氢（H2 S）是一种内源性信号气体分子，参与各种生理活动，包括血管松弛，细胞生物能调节，炎症和血管生成。通过使用异种移植原位植入前列腺癌PC3细胞，然后将骨转移与原发性肿瘤来源的癌细胞进行比较，我们发现产生H2 S的酶胱硫醚γ-裂合酶（CTH）在骨转移性PC3细胞中被上调。临床数据进一步表明，CTH的表达在晚期前列腺癌患者中升高，并且更高的CTH表达与癌症基因组图谱（TCGA）前列腺癌RNA-seq数据集的不良存活率相关。CTH通过H2 S介导的NF-κBp65亚基半胱氨酸38的巯基化作用促进NF-κB核转运，导致IL-1β表达增加和H2 S诱导的细胞侵袭。抑制PC3细胞中的CTH可抑制肿瘤生长和远处转移，而DU145细胞中CTH的过表达可促进原位植入异种移植小鼠模型中的原发性肿瘤生长和淋巴结转移。总之，我们的发现提供了证据，表明CTH产生的H2 S通过IL-1β/NF-κB信号通路促进了前列腺癌的进展和转移。

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Dysregulation of cystathionine γ-lyase promotes prostate cancer progression and metastasis.

Hydrogen sulfide (H2 S), an endogenous signaling gaseous molecule, is involved in various physiological activities, including vessel relaxation, regulation of cellular bioenergetics, inflammation, and angiogenesis. By using xenograft orthotopic implantation of prostate cancer PC3 cells and subsequently comparing bone metastatic with primary tumor-derived cancer cells, we find that H2 S-producing enzyme cystathionine γ-lyase (CTH) is upregulated in bone-metastatic PC3 cells. Clinical data further reveal that the expression of CTH is elevated in late-stage prostate cancer patients, and higher CTH expression correlates with poor survival from The Cancer Genome Atlas (TCGA) prostate cancer RNA-seq datasets. CTH promotes NF-κB nuclear translocation through H2 S-mediated sulfhydration on cysteine-38 of the NF-κB p65 subunit, resulting in increased IL-1β expression and H2 S-induced cell invasion. Knockdown of CTH in PC3 cells results in the suppression of tumor growth and distant metastasis, while overexpression of CTH in DU145 cells promotes primary tumor growth and lymph node metastasis in the orthotopic implanted xenograft mouse model. Together, our findings provide evidence that CTH generated H2 S promotes prostate cancer progression and metastasis through IL-1β/NF-κB signaling pathways.

更新日期：2019-10-04

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