Department of Oncology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, China.
J BUON. 2021 Jul-Aug;26(4):1279-1291.
Cervical cancer (CC) is the third most prevalent malignancy in women. Frizzled class receptor 6 (FZD6) is demonstrated to either activate or repress the activity of Wnt/β-catenin pathway, a crucial signaling involved in cancer development. However, the role of FZD6 in CC is unknown. The present study explored the function of FZD6 and its mechanism in CC.
The levels of FZD6, HOXC13-AS were detected in CC specimens and CC cell lines via qRT-PCR. Cell proliferation and invasion was explored via CCK-8 assay, colony formation assay and transwell assay. Luciferase reporter analysis, FISH, subcellular fractionation, chromatin immunoprecipitation and RNA immunoprecipitation were performed for investigating the molecular mechanism.
FZD6 was up-regulated in CC. FZD6 silence retarded proliferation, invasion, and epithelial-to-mesenchymal transition (EMT), and inactivated Wnt/β-catenin. HOXC13 antisense RNA (HOXC13-AS) was up-regulated in CC and positively correlated with FZD6. Mechanistically, HOCX13-AS1 augmented FZD through cAMP-response element binding protein-binding protein (CBP)-modulated histone H3 on lysine 27 acetylation (H3K27ac). Additionally, fat mass and obesity-associated protein (FTO) reduced N6-methyladenosine (m6A) and stabilized HOXC13-AS in CC.
In conclusion, this study firstly showed that FTO-stabilized HOXC13-AS epigenetically up-regulated FZD6 and activated Wnt/β-catenin signaling to drive CC proliferation, invasion, and EMT, suggesting HOXC13-AS as a potential target for CC treatment.
宫颈癌（CC）是女性中第三大常见恶性肿瘤。卷曲蛋白受体 6（FZD6）被证明可以激活或抑制 Wnt/β-连环蛋白通路的活性，该通路是癌症发展中关键的信号通路。然而，FZD6 在 CC 中的作用尚不清楚。本研究探讨了 FZD6 在 CC 中的功能及其机制。
通过 qRT-PCR 检测 CC 标本和 CC 细胞系中 FZD6 和 HOXC13-AS 的水平。通过 CCK-8 测定、集落形成测定和 Transwell 测定研究细胞增殖和侵袭。进行荧光素酶报告分析、FISH、亚细胞分级、染色质免疫沉淀和 RNA 免疫沉淀以研究分子机制。
FZD6 在 CC 中上调。FZD6 沉默抑制增殖、侵袭和上皮-间充质转化（EMT），并使 Wnt/β-连环蛋白失活。HOXC13 反义 RNA（HOXC13-AS）在 CC 中上调，并与 FZD6 呈正相关。机制上，HOCX13-AS1 通过 cAMP 反应元件结合蛋白结合蛋白（CBP）调节组蛋白 H3 赖氨酸 27 乙酰化（H3K27ac）增强 FZD6。此外，脂肪量和肥胖相关蛋白（FTO）降低 N6-甲基腺苷（m6A）并稳定 CC 中的 HOXC13-AS。
总之，本研究首次表明，FTO 稳定的 HOXC13-AS 通过表观遗传地上调 FZD6 并激活 Wnt/β-连环蛋白信号通路，驱动 CC 增殖、侵袭和 EMT，提示 HOXC13-AS 可作为 CC 治疗的潜在靶点。
