High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells.
High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells.
复制标题
高危 HPV16 E6 通过糖基转移酶 ST6GAL1 激活宫颈癌细胞中的 cGMP/PKG 通路。
DOI：
10.3389/fonc.2021.716246
复制
发表时间：
2021
影响因子：
4.7
通讯作者：
Xiang T
中科院分区：
文献类型：
--
作者：
Wang J;Liu G;Liu M;Cai Q;Yao C;Chen H;Song N;Yuan C;Tan D;Hu Y;Xiang Y;Xiang T
糖基化的改变调节癌症的基本分子和细胞过程，作为重要的生物标志物和治疗靶点。然而，E6癌蛋白对宫颈癌细胞糖基化的潜在关联和调控机制尚不清楚。在此，我们通过使用凝集素芯片评估糖组学变化，并确定与宫颈癌细胞中内源性高危HPV 16 E6表达相关的相应酶。在E6稳定表达HPV−宫颈癌C33 A细胞中，α-2，6唾液酸和相应的糖基转移酶ST 6 GAL 1显著增加。临床验证进一步显示，ST 6 GAL 1在高危型HPV亚型感染患者中表达显著增加，并在宫颈刮片样本中显示与E6正相关。干扰ST 6 GAL 1表达显著阻断E6对集落形成、增殖和转移的致癌作用。重要的是，ST 6 GAL 1过表达增强了E6阳性和E6阴性细胞的致瘤活性。机制研究表明，E6依赖于激活YAP 1来刺激ST 6 GAL 1的表达，因为维替泊芬（YAP 1的抑制剂）显著抑制E6诱导的ST 6 GAL 1上调。E6/ST 6 GAL 1激活下游cGMP/PKG信号通路，ODQ（GMP产生抑制剂）同时抑制E6和ST 6 GAL 1在宫颈癌细胞中的致癌活性。综上所述，这些研究结果表明，ST 6 GAL 1是致癌E6蛋白激活下游cGMP/PKG信号通路的重要介质，这代表了宫颈癌的新的分子机制和潜在的治疗靶点。
Alterations in glycosylation regulate fundamental molecular and cellular processes of cancer, serving as important biomarkers and therapeutic targets. However, the potential association and regulatory mechanisms of E6 oncoprotein on glycosylation of cervical cancer cells are still unclear. Here, we evaluated the glycomic changes via using Lectin microarray and determined the corresponding enzymes associated with endogenous high-risk HPV16 E6 expression in cervical cancer cells. α-2,6 sialic acids and the corresponding glycosyltransferase ST6GAL1 were significantly increased in E6 stable-expressing HPV− cervical cancer C33A cells. Clinical validation further showed that the expression of ST6GAL1 was significantly increased in patients infected with high-risk HPV subtypes and showed a positive association with E6 in cervical scraping samples. Interfering ST6GAL1 expression markedly blocked the oncogenic effects of E6 on colony formulation, proliferation, and metastasis. Importantly, ST6GAL1 overexpression enhanced tumorigenic activities of both E6-positive and E6-negative cells. Mechanistical investigations revealed that E6 depended on activating YAP1 to stimulate ST6GAL1 expression, as verteporfin (inhibitor of YAP1) significantly suppressed the E6-induced ST6GAL1 upregulation. E6/ST6GAL1 triggered the activation of downstream cGMP/PKG signaling pathway and ODQ (inhibitor of GMP production) simultaneously suppressed the oncogenic activities of both E6 and ST6GAL1 in cervical cancer cells. Taken together, these findings indicate that ST6GAL1 is an important mediator for oncogenic E6 protein to activate the downstream cGMP/PKG signaling pathway, which represents a novel molecular mechanism and potential therapeutic targets for cervical cancer.
登录
查看更多内容
DOI：
10.1073/pnas.1107385108
发表时间：
2011-07-12
影响因子：
11.1
作者：
Liu, Ying-Chih;Yen, Hsin-Yung;Wong, Chi-Huey
通讯作者：
Wong, Chi-Huey
影响因子：
50.3
作者：
Lee, Heng-Huan;Wang, Ying-Nai;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
影响因子：
9
作者：
Klutzny S;Anurin A;Nicke B;Regan JL;Lange M;Schulze L;Parczyk K;Steigemann P
通讯作者：
Steigemann P
影响因子：
3.4
作者：
Cisneros-Ramírez D;Martínez-Laguna Y;Martínez-Morales P;Aguilar-Lemarroy A;Jave-Suárez LF;Santos-López G;Reyes-Leyva J;Vallejo-Ruiz V
通讯作者：
Vallejo-Ruiz V
影响因子：
4.8
作者：
Long W;Yang Z;Li X;Chen M;Liu J;Zhang Y;Sun X
通讯作者：
Sun X