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Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1643-1648. doi: 10.1073/pnas.1620290114. Epub 2017 Jan 27.

YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis.

Taniguchi K1,2,3,4,5, Moroishi T6, de Jong PR7,8, Krawczyk M9, Grebbin BM10,11,12, Luo H9,13, Xu RH13, Golob-Schwarzl N14, Schweiger C14, Wang K1,2,3,15, Di Caro G1,2,3, Feng Y16, Fearon ER16,17,18, Raz E7, Kenner L19,20,21, Farin HF10,11,12, Guan KL6, Haybaeck J14,22, Datz C23, Zhang K9, Karin M24,2,3,25.

Author information

1
Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, CA 92093.
2
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
3
Department of Pathology, University of California, San Diego, La Jolla, CA 92093.
4
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
5
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
6
Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
7
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
8
Sanford Burnham Prebys Medical Discovery Institute, National Cancer Institute-Designated Cancer Center, La Jolla, CA 92037.
9
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093.
10
German Cancer Consortium, 69120 Heidelberg, Germany.
11
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt on Main, Germany.
12
German Cancer Research Center, 69120 Heidelberg, Germany.
13
State Key Laboratory of Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
14
Institute of Pathology, Medical University of Graz, Graz A-8036, Austria.
15
Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, 06030.
16
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
17
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109.
18
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
19
Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
20
Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, 1090 Vienna, Austria.
21
Department for Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
22
Department of Pathology, Otto-von-Guericke University of Magdeburg, 39120 Magdeburg, Germany.
23
Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, 5110 Oberndorf, Austria.
24
Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, CA 92093; karinoffice@ucsd.edu.
25
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.

Abstract

Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.

KEYWORDS:

IL-6ST/gp130; STAT3; YAP; adenomatous polyposis coli; colorectal cancer

PMID:
28130546
PMCID:
PMC5320959
DOI:
10.1073/pnas.1620290114
[Indexed for MEDLINE]
Free PMC Article

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