ATF6通过Hippo-YAP信号通路促进前列腺癌PC3细胞的增殖、迁移和侵袭

刘恒川; 杨宗珂; 刘清源; 张金栋; 朱辉轩; 王德林

doi:10.16016/j.2097-0927.202208013

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ATF6通过Hippo-YAP信号通路促进前列腺癌PC3细胞的增殖、迁移和侵袭

基础医学 | 更新时间：2026-01-09

- ATF6通过Hippo-YAP信号通路促进前列腺癌PC3细胞的增殖、迁移和侵袭
- Activating transcription factor 6 promotes proliferation, migration and invasion of PC3 human prostate cancer cells through Hippo-YAP signaling pathway
- 陆军军医大学学报 2023年45卷第1期页码：29-37
- 作者机构：
  
  1.400016 重庆，重庆医科大学附属第一医院泌尿外科
  2.408399 重庆，重庆市垫江县人民医院泌尿外科
- 作者简介：
  
  [王德林，E-mail：wangdlws@sina.comWANG Delin, E-mail: wangdlws@sina.com
- 基金信息：
  
  重庆市自然科学基金(cstc2019jcyj-msxmX0732);重庆市社会事业与民生保障科技创新专项(cstc2017shms-zdyf0319)
- DOI：10.16016/j.2097-0927.202208013
  中图分类号： R394.3;R73-37;R737.25
- 收稿：2022-08-02，
  
  修回：2022-09-09，
  
  纸质出版：2023-01-15
- 稿件说明：
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刘恒川, 杨宗珂, 刘清源, 等. ATF6通过Hippo-YAP信号通路促进前列腺癌PC3细胞的增殖、迁移和侵袭[J]. 陆军军医大学学报, 2023,45(1):29-37.

Hengchuan LIU, Zongke YANG, Qingyuan LIU, et al. Activating transcription factor 6 promotes proliferation, migration and invasion of PC3 human prostate cancer cells through Hippo-YAP signaling pathway[J]. Journal of Army Medical University, 2023, 45(1): 29-37.
刘恒川, 杨宗珂, 刘清源, 等. ATF6通过Hippo-YAP信号通路促进前列腺癌PC3细胞的增殖、迁移和侵袭[J]. 陆军军医大学学报, 2023,45(1):29-37. DOI： 10.16016/j.2097-0927.202208013.

Hengchuan LIU, Zongke YANG, Qingyuan LIU, et al. Activating transcription factor 6 promotes proliferation, migration and invasion of PC3 human prostate cancer cells through Hippo-YAP signaling pathway[J]. Journal of Army Medical University, 2023, 45(1): 29-37. DOI： 10.16016/j.2097-0927.202208013.

摘要

目的

探讨转录活化因子6 (activating transcription factor 6

ATF6)对前列腺癌PC3细胞增殖、迁移和侵袭的影响。

方法

收集前列腺癌组织标本和前列腺增生组织标本，实时荧光定量PCR(qRT-PCR)和Western blot分别检测ATF6的mRNA和蛋白质水平。通过shRNA慢病毒干扰载体感染PC3细胞，敲降ATF6表达水平。CCK8和EdU实验检测PC3细胞增殖能力，划痕实验和Transwell侵袭实验检测PC3细胞迁移和侵袭能力。采用裸鼠异种移植模型评估ATF6在体内对肿瘤增殖的影响。使用JASPAR数据库预测和荧光素酶报告基因评估Yes相关蛋白(YAP)和ATF6之间的关联。qRT-PCR、免疫荧光检测YAP的mRNA和蛋白质水平。qRT-PCR检测YAP的两个下游因子结缔组织生长因子(CTGF)和富含半胱氨酸的61(Cyr61)的mRNA表达水平。

结果

在前列腺癌组织中，ATF6的mRNA和蛋白质水平均显著升高(

0.05)。敲降ATF6后，PC3细胞的增殖能力、侵袭能力和迁移能力均受到抑制(

0.05)。动物实验证实敲降ATF6能明显抑制肿瘤生长(

0.05)。JASPAR数据库预测发现ATF6与YAP之前存在启动结合位点，荧光素酶报告基因证实ATF6与YAP存在相互作用。敲降ATF6后显著下调YAP的mRNA及蛋白质表达水平(

0.05)，且YAP下游基因CTGF和Cyr61的mRNA表达水平也随之下调(

0.05)。

结论

ATF6能通过Hippo-YAP信号通路促进前列腺癌PC3细胞的增殖、迁移和侵袭。

Abstract

Objective

To investigate the effects of activating transcription factor 6 (ATF6) on the proliferation

migration and invasion of prostate cancer PC3 cells.

Methods

Prostate cancer tissue samples and benign prostatic hyperplasia tissue samples were collected

then the mRNA and protein levels of ATF6 were detected by qRT-PCR and Western blotting

respectively. Lentivirus with ATF6 shRNA was transfected into PC3 cells to downregulate ATF6 expression

then CCK8 and EdU assays were adopted to determine the proliferation of PC3 cells

and wound-healing and Transwell invasion tests were performed to evaluate the migration and invasion abilities of PC3 cells. Nude mouse xenograft models were used to assess the influence of ATF6 on tumorigenesis

in vivo

. Moreover

the association between Yes-associated protein (YAP) and ATF6 was analyzed using online JASPAR database prediction and luciferase reporter. The mRNA and protein levels of YAP were detected with qRT-PCR and immunofluorescence assay

and the mRNA levels of 2 downstream factors of YAP

connective tissue growth factor (CTGF) and cysteine-rich 61 (Cyr61)

were also measured by qRT-PCR.

Results

The mRNA and protein levels of ATF6 in prostate cancer tissues were significantly increased (

0.05). Knockdown of ATF6 decreased the proliferation

invasion

and migration a

bilities of PC3 cells (

0.05)

and the

in vivo

study showed that ATF6-knockdown attenuated tumor growth as well (

0.05). JASPAR database predicted that there was an initiation binding site between ATF6 and YAP

and the luciferase reporter assay also confirmed the interaction between them. In addition

YAP expression was remarkably downregulated after knockdown of ATF6 (

0.05)

and the mRNA level of YAP downstream genes CTGF and Cyr61 were also decreased accordingly (

0.05).

Conclusion

ATF6 promotes the proliferation

migration

and invasion of prostate cancer PC3 cells through Hippo-YAP signaling pathway.

关键词

Keywords

references

SIEGEL R L, MILLER K D, FUCHS H E, et al . Cancer statistics, 2022[J ] . CA Cancer J Clin, 2022, 72(1): 7-33. DOI:10.3322/caac.21708.

CHEN W, ZHENG R, BAADE P D, et al . Cancer statistics in China, 2015[J ] . CA Cancer J Clin, 2016, 66(2): 115-132. DOI:10.3322/caac.21338.

REBELLO R J, OING C, KNUDSEN K E, et al . Prostate cancer[J ] . Nat Rev Dis Primers, 2021, 7: 9. DOI:10.1038/s41572-020-00243-0.

HILLARY R F, FITZGERALD U. A lifetime of stress: ATF 6 in development and homeostasis[J ] . J Biomed Sci, 2018, 25(1): 48. DOI:10.1186/s12929-018-0453-1.

YAMAMOTO K, YOSHIDA H, KOKAME K, et al . Differential contributions of ATF 6 and XBP 1 to the activation of endoplasmic Reticulum stress-responsive Cis-acting elements ERSE, UPRE and ERSE-Ⅱ[J ] . J Biochem, 2004, 136(3): 343-350. DOI:10.1093/jb/mvh122..

WU X P, XIN Z H, ZHANG W, et al . A missense polymorphism in ATF 6 gene is associated with susceptibility to hepatocellular carcinoma probably by altering ATF 6 level[J ] . Int J Cancer, 2014, 135(1): 61-68. DOI:10.1002/ijc.28649..

LIU C Y, HSU C C, HUANG T T, et al . ER stress-related ATF 6 upregulates CIP2A and contributes to poor prognosis of colon cancer[J ] . Mol Oncol, 2018, 12(10): 1706-1717. DOI:10.1002/1878-0261.12365..

SIWECKA N, ROZPEDEK W, PYTEL D, et al . Dual role of endoplasmic Reticulum stress-mediated unfolded protein response signaling pathway in carcinogenesis[J ] . Int J Mol Sci, 2019, 20(18): E4354. DOI:10.3390/ijms20184354.

LIU J N, XIAO M L, LI J J, et al . Activation of UPR signaling pathway is associated with the malignant progression and poor prognosis in prostate cancer[J ] . Prostate, 2017, 77(3): 274-281. DOI:10.1002/pros.23264.

ZANCONATO F, CORDENONSI M, PICCOLO S. YAP/TAZ at the roots of cancer[J]. Cancer Cell, 2016, 29(6): 783-803. DOI:10.1016/j.ccell.2016.05.005.

PANCIERA T, AZZOLIN L, CORDENONSI M, et al . Mechanobiology of YAP and TAZ in physiology and disease[J ] . Nat Rev Mol Cell Biol, 2017, 18(12): 758-770. DOI:10.1038/nrm.2017.87.

SHENG X, LI W B, WANG D L, et al . YAP is closely correlated with castration-resistant prostate cancer, and downregulation of YAP reduces proliferation and induces apoptosis of PC-3 cells[J ] . Mol Med Rep, 2015, 12(4): 4867-4876. DOI:10.3892/mmr.2015.4005.

WU H T, WEI L Y, FAN F Q, et al . Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis[J ] . Nat Commun, 2015, 6: 6239. DOI:10.1038/ncomms7239.

CASTRO-MONDRAGON J A, RIUDAVETS-PUIG R, RAULUSEVICIUTE I, et al . JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles[J ] . Nucleic Acids Res, 2021, 50(D1): D165-D173. DOI:10.1093/nar/gkab1113.

YU F X, ZHAO B, GUAN K L. Hippo pathway in organ size control, tissue homeostasis, and cancer[J]. Cell, 2015, 163(4): 811-828. DOI:10.1016/j.cell.2015.10.044.

GE L, SMAIL M, MENG W X, et al . Yes-associated protein expression in head and neck squamous cell carcinoma nodal metastasis[J ] . PLoS One, 2011, 6(11): e27529. DOI:10.1371/journal.pone.0027529.

WANG Y, DONG Q Z, ZHANG Q F, et al . Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer[J ] . Cancer Sci, 2010, 101(5): 1279-1285. DOI:10.1111/j.1349-7006.2010.01511.x.

XIA Y, CHANG T, WANG Y M, et al . YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients[J ] . PLoS One, 2014, 9(3): e91770. DOI:10.1371/journal.pone.0091770.

XU M Z, YAO T J, LEE N P, et al . Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma[J ] . Cancer, 2009, 115(19): 4576-4585. DOI:10.1002/cncr.24495.

CAO J J, ZHAO X M, WANG D L, et al . YAP is overexpressed in clear cell renal cell carcinoma and its knockdown reduces cell proliferation and induces cell cycle arrest and apoptosis[J ] . Oncol Rep, 2014, 32(4): 1594-1600. DOI:10.3892/or.2014.3349.

ZHANG L, YANG S P, CHEN X C, et al . The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells[J ] . Mol Cell Biol, 2015, 35(8): 1350-1362. DOI:10.1128/MCB.00102-15.

PAN Z J, TIAN Y Q, ZHANG B, et al . YAP signaling in gastric cancer-derived mesenchymal stem cells is critical for its promoting role in cancer progression[J ] . Int J Oncol, 2017, 51(4): 1055-1066. DOI:10.3892/ijo.2017.4101.

JIN X, ZHAO W C, ZHOU P, et al . YAP knockdown inhibits proliferation and induces apoptosis of human prostate cancer DU145 cells[J ] . Mol Med Rep, 2018, 17(3): 3783-3788. DOI:10.3892/mmr.2017.8352.

YU F X, ZHAO B, PANUPINTHU N, et al . Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling[J ] . Cell, 2012, 150(4): 780-791. DOI:10.1016/j.cell.2012.06.037.

RIVERA-REYES A, YE S, E MARINO G, et al . YAP1 enhances NF-κB-dependent and independent effects on clock-mediated unfolded protein responses and autophagy in sarcoma[J ] . Cell Death Dis, 2018, 9: 1108. DOI:10.1038/s41419-018-1142-4.

CHENG T Y, WU M S, HUA K T, et al . Cyr61/CTGF/Nov family proteins in gastric carcinogenesis[J ] . World J Gastroenterol, 2014, 20(7): 1694-1700. DOI:10.3748/wjg.v20.i7.1694.

HSU Y L, HUNG J Y, CHOU S H, et al . Angiomotin decreases lung cancer progression by sequestering oncogenic YAP/TAZ and decreasing Cyr61 expression[J ] . Oncogene, 2015, 34(31): 4056-4068. DOI:10.1038/onc.2014.333.

LAI D, HO K C, HAO Y W, et al . Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF[J ] . Cancer Res, 2011, 71(7): 2728-2738. DOI:10.1158/0008-5472.CAN-10-2711.

SHOME D, VON WOEDTKE T, RIEDEL K, et al . The HIPPO transducer YAP and its targets CTGF and Cyr61 drive a paracrine signalling in cold atmospheric plasma-mediated wound healing[J ] . Oxid Med Cell Longev, 2020, 2020: 4910280. DOI:10.1155/2020/4910280.

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