KRAS Mutation Leads to Decreased Expression of Regulator of Calcineurin 2, Resulting in Tumor Proliferation in Colorectal Cancer

Overview

Journal Oncogenesis

Date 2016 Aug 16

PMID 27526107

Citations 17

Authors

H Niitsu

T Hinoi

Y Kawaguchi

K Sentani

R Yuge

Y Kitadai

Y Sotomaru

T Adachi

Y Saito

M Miguchi

M Kochi

H Sada

M Shimomura

N Oue

W Yasui

H Ohdan

Affiliations

Soon will be listed here.

Abstract

KRAS mutations occur in 30-40% of all cases of human colorectal cancer (CRC). However, to date, specific therapeutic agents against KRAS-mutated CRC have not been developed. We previously described the generation of mouse models of colon cancer with and without Kras mutations (CDX2P-G22Cre;Apc(flox/flox); LSL-Kras(G12D) and CDX2P-G22Cre;Apc(flox/flox) mice, respectively). Here, the two mouse models were compared to identify candidate genes, which may represent novel therapeutic targets or predictive biomarkers. Differentially expressed genes in tumors from the two mouse models were identified using microarray analysis, and their expression was compared by quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemical analyses in mouse tumors and surgical specimens of human CRC, with or without KRAS mutations, respectively. Furthermore, the functions of candidate genes were studied using human CRC cell lines. Microarray analysis of 34 000 transcripts resulted in the identification of 19 candidate genes. qRT-PCR analysis data showed that four of these candidate genes (Clps, Irx5, Bex1 and Rcan2) exhibited decreased expression in the Kras-mutated mouse model. The expression of the regulator of calcineurin 2 (RCAN2) was also observed to be lower in KRAS-mutated human CRC. Moreover, inhibitory function for cancer cell proliferation dependent on calcineurin was indicated with overexpression and short hairpin RNA knockdown of RCAN2 in human CRC cell lines. KRAS mutations in CRC lead to a decrease in RCAN2 expression, resulting in tumor proliferation due to derepression of calcineurin-nuclear factor of activated T cells (NFAT) signaling. Our findings suggest that calcineurin-NFAT signal may represent a novel molecular target for the treatment of KRAS-mutated CRC.

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References

Hinoi T, Lucas P, Kuick R, Hanash S, Cho K, Fearon E . CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia. Gastroenterology. 2002; 123(5):1565-77. DOI: 10.1053/gast.2002.36598. View

Sasada T, Hinoi T, Saito Y, Adachi T, Takakura Y, Kawaguchi Y . Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice. PLoS One. 2015; 10(7):e0132435. PMC: 4505894. DOI: 10.1371/journal.pone.0132435. View

Liu X, Zhao D, Qin L, Li J, Zeng H . Transcription enhancer factor 3 (TEF3) mediates the expression of Down syndrome candidate region 1 isoform 1 (DSCR1-1L) in endothelial cells. J Biol Chem. 2008; 283(49):34159-67. PMC: 2662233. DOI: 10.1074/jbc.M806338200. View

Masuo T, Okamura S, Zhang Y, Mori M . Cyclosporine A inhibits colorectal cancer proliferation probably by regulating expression levels of c-Myc, p21(WAF1/CIP1) and proliferating cell nuclear antigen. Cancer Lett. 2009; 285(1):66-72. DOI: 10.1016/j.canlet.2009.05.001. View

Bardelli A, Siena S . Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010; 28(7):1254-61. DOI: 10.1200/JCO.2009.24.6116. View

Rao A, Luo C, Hogan P . Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol. 1997; 15:707-47. DOI: 10.1146/annurev.immunol.15.1.707. View

Duque J, Fresno M, Iniguez M . Expression and function of the nuclear factor of activated T cells in colon carcinoma cells: involvement in the regulation of cyclooxygenase-2. J Biol Chem. 2005; 280(10):8686-93. DOI: 10.1074/jbc.M413076200. View

Miyazaki T, Kanou Y, Murata Y, Ohmori S, Niwa T, Maeda K . Molecular cloning of a novel thyroid hormone-responsive gene, ZAKI-4, in human skin fibroblasts. J Biol Chem. 1996; 271(24):14567-71. DOI: 10.1074/jbc.271.24.14567. View

Shibasaki F, Price E, Milan D, McKeon F . Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4. Nature. 1996; 382(6589):370-3. DOI: 10.1038/382370a0. View

10.

Fuentes J, Genesca L, Kingsbury T, Cunningham K, Estivill X, de la Luna S . DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet. 2000; 9(11):1681-90. DOI: 10.1093/hmg/9.11.1681. View

11.

Workman P, Aboagye E, Balkwill F, Balmain A, Bruder G, Chaplin D . Guidelines for the welfare and use of animals in cancer research. Br J Cancer. 2010; 102(11):1555-77. PMC: 2883160. DOI: 10.1038/sj.bjc.6605642. View

12.

Vaughn C, Zobell S, Furtado L, Baker C, Samowitz W . Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer. 2011; 50(5):307-12. DOI: 10.1002/gcc.20854. View

13.

Heinemann V, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran S . FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014; 15(10):1065-75. DOI: 10.1016/S1470-2045(14)70330-4. View

14.

Hinoi T, Akyol A, Theisen B, Ferguson D, Greenson J, Williams B . Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Res. 2007; 67(20):9721-30. DOI: 10.1158/0008-5472.CAN-07-2735. View

15.

Qin L, Zhao D, Liu X, Nagy J, Hoang M, Brown L . Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway. Mol Cancer Res. 2006; 4(11):811-20. DOI: 10.1158/1541-7786.MCR-06-0126. View

16.

Akyol A, Hinoi T, Feng Y, Bommer G, Glaser T, Fearon E . Generating somatic mosaicism with a Cre recombinase-microsatellite sequence transgene. Nat Methods. 2008; 5(3):231-3. PMC: 2279183. DOI: 10.1038/nmeth.1182. View

17.

Schulz R, Yutzey K . Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development. Dev Biol. 2004; 266(1):1-16. DOI: 10.1016/j.ydbio.2003.10.008. View

18.

Fuentes J, Pritchard M, Planas A, Bosch A, Ferrer I, Estivill X . A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum Mol Genet. 1995; 4(10):1935-44. DOI: 10.1093/hmg/4.10.1935. View

19.

Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H . Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009; 325(5947):1555-9. PMC: 2820374. DOI: 10.1126/science.1174229. View

20.

Canaider S, Vettraino M, Norling L, Spisni E, Facchin F, Cooper D . Human RCAN3 gene expression and cell growth in endothelial cells. Int J Mol Med. 2010; 26(6):913-8. DOI: 10.3892/ijmm_00000542. View