GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells

Shu Z. Wiley, Krishna Sriram, Wenjing Liang, Sarah E. Chang, Randall French, Thalia McCann, Jason Sicklick, Hiroshi Nishihara, Andrew M. Lowy, Paul A. Insel

研究成果: Article査読

55 被引用数 (Scopus)

抄録

Themicroenvironment of pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma (desmoplasia) generated by pancreatic cancer-associated fibroblasts (CAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). Using an unbiased GPCRomic array approach, we identified 82 G-protein-coupled receptors (GPCRs) commonly expressed by CAFs derived from 5 primary PDAC tumors. Comparedwith PSCs and PFs, CAFs have increased expression ofGPR68 (a proton-sensingGPCR), with the results confirmed by immunoblotting, The Cancer Genome Atlas data, and immunohistochemistry of PDAC tumors. Coculture of PSCs with PDAC cells, or incubation with TNF-α, induced GPR68 expression. GPR68 activation (by decreasing the extracellular pH) enhanced IL-6 expression via a cAMP/PKA/cAMP response element binding protein signaling pathway. Knockdown of GPR68 by short interfering RNA diminished low pH-induced production of IL-6 and enhancement of PDAC cell proliferation by CAF conditioned media. CAFs from other gastrointestinal cancers also express GPR68. PDAC cells thus induce expression by CAFs of GPR68, which senses the acidic microenvironment, thereby increasing production of fibrotic markers and IL-6 and promoting PDAC cell proliferation. CAF-expressed GPR68 is a mediator of low-pH-promoted regulation of the tumor microenvironments, in particular to PDAC cell-CAF interaction and may be a novel therapeutic target for pancreatic and perhaps other types of cancers.

本文言語English
ページ(範囲)1170-1183
ページ数14
ジャーナルFASEB Journal
32
3
DOI
出版ステータスPublished - 2018 3月
外部発表はい

ASJC Scopus subject areas

  • バイオテクノロジー
  • 生化学
  • 分子生物学
  • 遺伝学

フィンガープリント

「GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル