TGF-β 信号通过 CDR1as 促进宫颈癌转移。

TGF-β signaling promotes cervical cancer metastasis via CDR1as.

机构信息

Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang West Road, Guangzhou, People's Republic of China, 510120.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.

出版信息

Mol Cancer. 2023 Mar 31;22(1):66. doi: 10.1186/s12943-023-01743-9.

BACKGROUND

Due to the lack of effective treatment, metastasis is the main cause of cancer related deaths. TGF-β pathway has been reported related to cervical cancer metastasis. However, mechanism is still unclear.

METHODS

After agonist of TGF-β treatment, RNA sequencing revealed the expression profiles of circRNA in cervical cancer. In situ hybridization was used to analysis relationship between CDR1as and prognosis. Real-time PCR, Western blot, RNA interference, Transwell assay, Wound healing assay, RNA pulldown assay and RIP assays were performed in vitro. And in vivo cervical cancer model (including foot pad model and subcutaneous tumor formation) was also performed.

RESULTS

CDR1as was found upregulated obviously following TGF-β activation. In situ hybridization showed CDR1as was positively correlated with lymph node metastasis and shortened survival length. Simultaneously, overexpression of CDR1as promoted cervical cancer metastasis in vitro and in vivo. It was also found that CDR1as could facilitate the orchestration of IGF2BP1 on the mRNA of SLUG and stabilize it from degradation. Silencing IGF2BP1 hampers CDR1as related metastasis in cervical cancer. Additionally, effective CDR1as has been proven to activate TGF-β signaling factors known to promote EMT, including P-Smad2 and P-Smad3.

CONCLUSIONS

Our study proved TGF-β signaling may promote cervical cancer metastasis via CDR1as.

背景

由于缺乏有效的治疗方法，转移是癌症相关死亡的主要原因。TGF-β 途径已被报道与宫颈癌转移有关。然而，其机制尚不清楚。

方法

在 TGF-β 激动剂处理后，RNA 测序揭示了宫颈癌中 circRNA 的表达谱。采用原位杂交分析 CDR1as 与预后的关系。在体外进行实时 PCR、Western blot、RNA 干扰、Transwell 测定、划痕愈合测定、RNA 下拉测定和 RIP 测定。还进行了体内宫颈癌模型（包括足底模型和皮下肿瘤形成）。

结果

发现 TGF-β 激活后 CDR1as 明显上调。原位杂交显示 CDR1as 与淋巴结转移呈正相关，并缩短了生存时间。同时，CDR1as 的过表达促进了宫颈癌在体外和体内的转移。还发现 CDR1as 可以促进 IGF2BP1 在 SLUG mRNA 上的协调作用，并稳定其免受降解。沉默 IGF2BP1 可阻碍宫颈癌中 CDR1as 相关的转移。此外，已证明有效的 CDR1as 可激活 TGF-β 信号转导因子，已知这些因子可促进 EMT，包括 P-Smad2 和 P-Smad3。