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上调的GPRC5A破坏Hippo信号通路，通过cAMP-CREB轴促进胰腺癌细胞的增殖和迁移。

Upregulated GPRC5A disrupting the Hippo pathway promotes the proliferation and migration of pancreatic cancer cells via the cAMP-CREB axis.

作者信息

Fang Weidan, Yu Xin, Deng Jun, Yu Bin, Xiong Jianping, Ma Mei

机构信息

Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.

Jiangxi Key Laboratory for Individualized Cancer Therapy, Nanchang, China.

出版信息

Discov Oncol. 2023 Feb 3;14(1):17. doi: 10.1007/s12672-023-00626-1.

DOI:10.1007/s12672-023-00626-1
PMID:36735162
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9898488/
Abstract

BACKGROUND

Pancreatic cancer has a high mortality rate worldwide, and is predicted to be third leading cause of death in the near future. However, the regulatory mechanisms that inhibit the progression of pancreatic cancer remain elusive. Currently, exploring the function and mechanisms of GPCRs (G-protein coupled receptors) is an important way to discover promising therapeutic targets for cancer.

METHODS

GPRC5A expression was measured using real-time quantitative PCR, immunohistochemistry and western blot assays. Cell proliferation and migration were assessed using CCK-8, clone formation, wound-healing and transwell assays. A cytosolic/nuclear distribution experiment was used to detect the protein location transfer. A xenograft model of pancreatic cancer was established to explore the role of GPRC5A in vivo.

RESULTS

GPRC5A expression was increased in pancreatic cancer, and disruption of GPRC5A expression inhibited tumor growth in vivo. Mechanistically, GPRC5A positively regulated the transcription of YAP1 through cAMP-CREB signaling. Moreover, we show that the proliferation and migration induced by GPRC5A in pancreatic cancer could be rescued by inhibiting YAP1 expression.

CONCLUSIONS

GPRC5A interacts with the Hippo pathway to promote the progression of pancreatic cancer. These findings reveal an important crosstalk model and provide potential targets for pancreatic cancer therapy.

摘要

背景

胰腺癌在全球范围内具有较高的死亡率，预计在不久的将来将成为第三大死因。然而，抑制胰腺癌进展的调控机制仍不清楚。目前，探索G蛋白偶联受体（GPCRs）的功能和机制是发现有前景的癌症治疗靶点的重要途径。

方法

采用实时定量PCR、免疫组织化学和蛋白质印迹分析检测GPRC5A的表达。使用CCK-8、克隆形成、伤口愈合和Transwell实验评估细胞增殖和迁移。采用胞质/核分布实验检测蛋白定位转移。建立胰腺癌异种移植模型以探讨GPRC5A在体内的作用。

结果

胰腺癌中GPRC5A表达增加，破坏GPRC5A表达可抑制体内肿瘤生长。机制上，GPRC5A通过cAMP-CREB信号通路正向调节YAP1的转录。此外，我们发现抑制YAP1表达可挽救GPRC5A诱导的胰腺癌增殖和迁移。

结论

GPRC5A与Hippo通路相互作用促进胰腺癌进展。这些发现揭示了一种重要的串扰模型，并为胰腺癌治疗提供了潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/38b07583eaa9/12672_2023_626_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/a361964cea57/12672_2023_626_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/9f7956245bd5/12672_2023_626_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/b4c383494ca5/12672_2023_626_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/04d33bf8e744/12672_2023_626_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/f006435999bc/12672_2023_626_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/6a605777244d/12672_2023_626_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/38b07583eaa9/12672_2023_626_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/a361964cea57/12672_2023_626_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/9f7956245bd5/12672_2023_626_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/b4c383494ca5/12672_2023_626_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/04d33bf8e744/12672_2023_626_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/f006435999bc/12672_2023_626_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/6a605777244d/12672_2023_626_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a130/9898488/38b07583eaa9/12672_2023_626_Fig7_HTML.jpg

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