Notch signaling via regulation of RB and p‑AKT but not PIK3CG contributes to MIA PaCa‑2 cell growth and migration to affect pancreatic carcinogenesis

Zhang,Shubing; Liu,Jingjiang; Xu,Keli; Li,Zhijian

doi:10.3892/ol.2017.7551

Notch signaling via regulation of RB and p‑AKT but not PIK3CG contributes to MIA PaCa‑2 cell growth and migration to affect pancreatic carcinogenesis

Authors:
- Shubing Zhang
- Jingjiang Liu
- Keli Xu
- Zhijian Li
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Affiliations: Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China, Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan 410011, P.R. China, Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA, Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 41001, P.R. China
Published online on: December 8, 2017 https://doi.org/10.3892/ol.2017.7551
Pages: 2105-2110
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pancreatic cancer is one of the leading causes of cancer‑associated mortality. The understanding of the expression pattern of key protein factors and their function in pancreatic cancer cells is therefore vital for the diagnosis and treatment of this malignancy. The results of the present study reveal that the levels of neurogenic locus notch homolog protein 2 (Notch2) and phosphorylated (p)‑SMAD family member 2 decreased, whereas the expression of Notch3 and phosphoinositide‑3 kinase catalytic subunit‑γ protein increased in human pancreatic cancer tissues compared with tumor‑adjacent tissues. Using the human pancreatic cancer MIA PaCa‑2 cell line, it was observed that retinoblastoma-associated protein (RB) and p‑RB expression were inhibited and p‑AKT was upregulated when Notch signaling was activated in MIA PaCa‑2 cells. Furthermore, inhibition of phosphoinositide‑3 kinase catalytic subunit‑γ (PIK3CG) activity by AS‑605240 was able to block the growth and migration of MIA PaCa‑2 cells. In conclusion, the results of the present study demonstrate that the Notch signal pathway may be involved in pancreatic carcinogenesis by modulating RB and p‑AKT. PIK3CG may therefore be a potential target gene for the treatment of pancreatic cancer.

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1	Chen Huang, Jiawei Du and Keping Xie: FOXM1 and its oncogenic signaling in pancreatic cancer pathogenesis. Biochim Biophys Acta. 1845:104–116. 2014.PubMed/NCBI
2	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
3	Zhang S, Chung WC and Xu K: Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer. Oncogene. 35:2485–2495. 2016. View Article : Google Scholar : PubMed/NCBI
4	Boyle J, Czito B, Willett C and Palta M: Adjuvant radiation therapy for pancreatic cancer: a review of the old and the new. J Gastrointest Oncol. 6:436–444. 2015.PubMed/NCBI
5	Kunnimalaiyaan S, Trevino J, Tsai S, Gamblin TC and Kunnimalaiyaan M: Xanthohumol-mediated suppression of Notch1 signaling is associated with antitumor activity in human pancreatic cancer cells. Mol Cancer Ther. 14:1395–1403. 2015. View Article : Google Scholar : PubMed/NCBI
6	Marechal R, Bachet JB, Calomme A, Demetter P, Delpero JR, Svrcek M, Cros J, Bardier-Dupas A, Puleo F, Monges G, et al: Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. Clin Cancer Res. 21:1215–1224. 2015. View Article : Google Scholar : PubMed/NCBI
7	Jiang S, Zhu L, Tang H, Zhang M, Chen Z, Fei J, Han B and Zou GM: Ape1 regulates WNT/β-catenin signaling through its redox functional domain in pancreatic cancer cells. Int J Oncol. 47:610–620. 2015. View Article : Google Scholar : PubMed/NCBI
8	Court H, Amoyel M, Hackman M, Lee KE, Xu R, Miller G, Bar-Sagi D, Bach EA, Bergo MO and Philips MR: Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression. J Clin Invest. 123:4681–4694. 2013. View Article : Google Scholar : PubMed/NCBI
9	Hanlon L, Avila JL, Demarest RM, Troutman S, Allen M, Ratti F, Rustgi AK, Stanger BZ, Radtke F, Adsay V, et al: Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Res. 70:4280–4286. 2010. View Article : Google Scholar : PubMed/NCBI
10	Mazur PK, Einwachter H, Lee M, Sipos B, Nakhai H, Rad R, Zimber-Strobl U, Strobl LJ, Radtke F, Klöppel G, et al: Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA. 107:pp. 13438–13443. 2010; View Article : Google Scholar : PubMed/NCBI
11	Zhao HF, Wang J and Tony To SS: The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? (Review). Int J Oncol. 47:429–436. 2015. View Article : Google Scholar : PubMed/NCBI
12	Manceau G, Marisa L, Boige V, Duval A, Gaub MP, Milano G, Selves J, Olschwang S, Jooste V, le Legrain M, et al: PIK3CA mutations predict recurrence in localized microsatellite stable colon cancer. Cancer Med. 4:371–382. 2015. View Article : Google Scholar : PubMed/NCBI
13	Martin D, Galisteo R, Molinolo AA, Wetzker R, Hirsch E and Gutkind JS: PI3Kγ mediates kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis. Cancer Cell. 19:805–813. 2011. View Article : Google Scholar : PubMed/NCBI
14	Li Y, Wang K, Jiang YZ, Chang XW, Dai CF and Zheng J: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits human ovarian cancer cell proliferation. Cell Oncol (Dordr). 37:429–437. 2014. View Article : Google Scholar : PubMed/NCBI
15	Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, et al: COSMIC: Mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res. 39((Database Issue): D945–D950. 2011. View Article : Google Scholar : PubMed/NCBI
16	Zhang S, Chung WC, Wu G, Egan SE, Miele L and Xu K: Manic fringe promotes a claudin-low breast cancer phenotype through notch-mediated PIK3CG induction. Cancer Res. 75:1936–1943. 2015. View Article : Google Scholar : PubMed/NCBI
17	Murphree AL and Benedict WF: Retinoblastoma: Clues to human oncogenesis. Science. 223:1028–1033. 1984. View Article : Google Scholar : PubMed/NCBI
18	Schaal C, Pillai S and Chellappan SP: The Rb-E2F transcriptional regulatory pathway in tumor angiogenesis and metastasis. Adv Cancer Res. 121:147–182. 2014. View Article : Google Scholar : PubMed/NCBI
19	Gore AJ, Deitz SL, Palam LR, Craven KE and Korc M: Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-γ to promote proliferation. J Clin Invest. 124:338–352. 2014. View Article : Google Scholar : PubMed/NCBI
20	Carriere C, Gore AJ, Norris AM, Gunn JR, Young AL, Longnecker DS and Korc M: Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions. Gastroenterology. 141:1091–1101. 2011. View Article : Google Scholar : PubMed/NCBI
21	Kagawa S, Natsuizaka M, Whelan KA, Facompre N, Naganuma S, Ohashi S, Kinugasa H, Egloff AM, Basu D, Gimotty PA, et al: Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities. Oncogene. 34:2347–2359. 2015. View Article : Google Scholar : PubMed/NCBI
22	Li Y, Zhao YJ, Zou QY, Zhang K, Wu YM, Zhou C, Wang K and Zheng J: Preeclampsia does not alter vascular growth and expression of CD31 and vascular endothelial cadherin in human placentas. J Histochem Cytochem. 63:22–31. 2015. View Article : Google Scholar : PubMed/NCBI
23	Zhao YJ, Zou QY, Li Y, Li HH, Wu YM, Li XF, Wang K and Zheng J: Expression of G-protein subunit γ-14 is increased in human placentas from preeclamptic pregnancies. J Histochem Cytochem. 62:347–354. 2014. View Article : Google Scholar : PubMed/NCBI
24	Zhao Z, Song Y, Piao D, Liu T and Zhao L: Identification of genes and long non-coding RNAs associated with the pathogenesis of gastric cancer. Oncol Rep. 34:1301–1310. 2015. View Article : Google Scholar : PubMed/NCBI
25	Bailey JM, Alsina J, Rasheed ZA, McAllister FM, Fu YY, Plentz R, Zhang H, Pasricha PJ, Bardeesy N, Matsui W, et al: DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology. 146:245–1256. 2014. View Article : Google Scholar : PubMed/NCBI
26	Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, Wolfe MS, et al: Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell. 3:565–576. 2003. View Article : Google Scholar : PubMed/NCBI
27	Mann CD, Bastianpillai C, Neal CP, Masood MM, Jones DJ, Teichert F, Singh R, Karpova E, Berry DP and Manson MM: Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma. PLoS One. 7:e511192012. View Article : Google Scholar : PubMed/NCBI