p38 predicts depression and poor outcome in esophageal cancer

Cheng,Yao; Qiao,Zhe; Dang,Chengxue; Zhou,Bin; Li,Shaomin; Zhang,Wei; Jiang,Jiantao; Song,Yongchun; Zhang,Jin; Diao,Dongmei

doi:10.3892/ol.2017.7129

p38 predicts depression and poor outcome in esophageal cancer

Authors:
- Yao Cheng
- Zhe Qiao
- Chengxue Dang
- Bin Zhou
- Shaomin Li
- Wei Zhang
- Jiantao Jiang
- Yongchun Song
- Jin Zhang
- Dongmei Diao
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Affiliations: Department of Thoracic Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710004, P.R. China, Department of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, P.R. China
Published online on: October 3, 2017 https://doi.org/10.3892/ol.2017.7129
Pages: 7241-7249
Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

p38 mitogen‑activated protein kinase (MAPK) signaling has been implicated in the cancer development and progression. However, the precise mechanism of this association remains unknown. The aim of the present study was to evaluate the association between p38 and cancer progression, including investigations into the effects on cell proliferation, resistance to thalidomide, indoleamine 2,3‑dioxygenase (IDO) expression and prognosis in patients with esophageal cancer. The present retrospective study included patients with stage I‑III esophageal cancer. A total of 228 patients with esophageal cancer were recruited to analyze the expression of phosphorylated (p)‑p38 and IDO in tumor, and normal tissues through immunohistochemistry. Depression status was measured using the Zung Self‑Rating Depression Scale. P38 cDNA was transfected into esophageal cancer cells to assess tumor cell viability, sensitivity to thalidomide treatment and IDO gene expression. Western blotting and flow cytometry was used to analyze protein expression alterations, and apoptosis in esophageal cancer cells. P‑p38 protein was expressed in 68.9% of cancer tissues, and was significantly associated with depressive symptoms, tumor recurrence and poor survival of patients. In vitro experiments revealed that the expression of p‑p38 induced esophageal cancer Eca‑109 and TE‑1 cell viability, and resistance to thalidomide treatment, as well as in the expression of IDO without the application of lipopolysaccharides. Further follow‑up of patients revealed that depression was also an independent factor for early recurrence and overall survival rate. Altered p38 MAPK expression was associated with poor outcome in patients with esophageal cancer. p38 may be a potential biomarker for the prediction of depressive symptoms and prognosis in patients with esophageal cancer.

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1	Rubenstein JH and Shaheen NJ: Epidemiology, diagnosis, and management of esophageal adenocarcinoma. Gastroenterology. 149:302–317. 2015. View Article : Google Scholar : PubMed/NCBI
2	Mortensen MB: Avoiding complications in esophageal cancer surgery. Minerva Chir. 68:341–352. 2013.PubMed/NCBI
3	Brescia AA, Broderick SR, Crabtree TD, Puri V, Musick JF, Bell JM, Kreisel D, Krupnick AS, Patterson GA and Meyers BF: Adjuvant therapy for positive nodes after induction therapy and resection of esophageal cancer. Ann Thorac Surg. 101:200–210. 2016. View Article : Google Scholar : PubMed/NCBI
4	Pozza A, Erroi FR, Scarpa M, Polese L, Rampazzo L and Norberto L: Palliative therapy for esophageal cancer: Laser therapy alone is associated with a better functional outcome. Updates Surg. 67:61–67. 2015. View Article : Google Scholar : PubMed/NCBI
5	Wilson KG, Chochinov HM, Skirko MG, Allard P, Chary S, Gagnon PR, Macmillan K, De Luca M, O'Shea F, Kuhl D, et al: Depression and anxiety disorders in palliative cancer care. J Pain Symptom Manage. 33:118–129. 2007. View Article : Google Scholar : PubMed/NCBI
6	Grabsch B, Clarke DM, Love A, McKenzie DP, Snyder RD, Bloch S, Smith G and Kissane DW: Psychological morbidity and quality of life in women with advanced breast cancer: A cross-sectional survey. Palliat Support Care. 4:47–56. 2006. View Article : Google Scholar : PubMed/NCBI
7	Pelletier G, Verhoef MJ, Khatri N and Hagen N: Quality of life in brain tumor patients: The relative contributions of depression, fatigue, emotional distress, and existential issues. J Neurooncol. 57:41–49. 2002. View Article : Google Scholar : PubMed/NCBI
8	Breitbart W: Identifying patients at risk for, and treatment of major psychiatric complications of cancer. Support Care Cancer. 3:45–60. 1995. View Article : Google Scholar : PubMed/NCBI
9	Irving G and Lloyd-Williams M: Depression in advanced cancer. Eur J Oncol Nurs. 14:395–399. 2010. View Article : Google Scholar : PubMed/NCBI
10	Kadan-Lottick NS, Vanderwerker LC, Block SD, Zhang B and Prigerson HG: Psychiatric disorders and mental health service use in patients with advanced cancer: A report from the coping with cancer study. Cancer. 104:2872–2881. 2005. View Article : Google Scholar : PubMed/NCBI
11	Kumar B, Koul S, Petersen J, Khandrika L, Hwa JS, Meacham RB, Wilson S and Koul HK: p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Res. 70:832–841. 2010. View Article : Google Scholar : PubMed/NCBI
12	Xiong S, Grijalva R, Zhang L, Nguyen NT, Pisters PW, Pollock RE and Yu D: Up-regulation of vascular endothelial growth factor in breast cancer cells by the heregulin-beta1-activated p38 signaling pathway enhances endothelial cell migration. Cancer Res. 61:1727–1732. 2001.PubMed/NCBI
13	Kumar V, Behera R, Lohite K, Karnik S and Kundu GC: p38 kinase is crucial for osteopontin-induced furin expression that supports cervical cancer progression. Cancer Res. 70:10381–10391. 2010. View Article : Google Scholar : PubMed/NCBI
14	Guo X, Ma N, Wang J, Song J, Bu X, Cheng Y, Sun K, Xiong H, Jiang G, Zhang B, et al: Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells. BMC Cancer. 8:3752008. View Article : Google Scholar : PubMed/NCBI
15	Coltella N, Rasola A, Nano E, Bardella C, Fassetta M, Filigheddu N, Graziani A, Comoglio PM and Di Renzo MF: p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy-induced apoptosis. Int J Cancer. 118:2981–2990. 2006. View Article : Google Scholar : PubMed/NCBI
16	Looby E, Abdel-Latif MM, Athié-Morales V, Duggan S, Long A and Kelleher D: Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells. BMC Cancer. 9:1902009. View Article : Google Scholar : PubMed/NCBI
17	Yousif NG, Al-Amran FG, Hadi N, Lee J and Adrienne J: Expression of IL-32 modulates NF-κB and p38 MAP kinase pathways in human esophageal cancer. Cytokine. 61:223–227. 2013. View Article : Google Scholar : PubMed/NCBI
18	Zhong D, Gu C, Shi L, Xun T, Li X, Liu S and Yu L: Obatoclax induces G1/G0-phase arrest via p38/p21(waf1/Cip1) signaling pathway in human esophageal cancer cells. J Cell Biochem. 115:1624–1635. 2014. View Article : Google Scholar : PubMed/NCBI
19	Zoga M, Oulis P, Chatzipanagiotou S, Masdrakis VG, Pliatsika P, Boufidou F, Foteli S, Soldatos CR, Nikolaou C and Papageorgiou C: Indoleamine 2,3-dioxygenase and immune changes under antidepressive treatment in major depression in females. In Vivo. 28:633–638. 2014.PubMed/NCBI
20	Zhou W, Dantzer R, Budac DP, Walker AK, Mao-Ying QL, Lee AW, Heijnen CJ and Kavelaars A: Peripheral indoleamine 2,3-dioxygenase 1 is required for comorbid depression-like behavior but does not contribute to neuropathic pain in mice. Brain Behav Immun. 46:147–153. 2015. View Article : Google Scholar : PubMed/NCBI
21	Liu WL, Lin YH, Xiao H, Xing S, Chen H, Chi PD and Zhang G: Epstein-Barr virus infection induces indoleamine 2,3-dioxygenase expression in human monocyte-derived macrophages through p38/mitogen-activated protein kinase and NF-κB pathways: Impairment in T cell functions. J Virol. 88:6660–6671. 2014. View Article : Google Scholar : PubMed/NCBI
22	Fujigaki H, Saito K, Fujigaki S, Takemura M, Sudo K, Ishiguro H and Seishima M: The signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 are not essential for the induction of indoleamine 2,3-dioxygenase by lipopolysaccharide: Involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways, and synergistic effect of several proinflammatory cytokines. J Biochem. 139:655–662. 2006. View Article : Google Scholar : PubMed/NCBI
23	Fu X, Lawson MA, Kelley KW and Dantzer R: HIV-1 Tat activates indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures in a p38 mitogen-activated protein kinase-dependent manner. J Neuroinflammation. 8:882011. View Article : Google Scholar : PubMed/NCBI
24	Nomura M, Shitara K, Kodaira T, Hatooka S, Mizota A, Kondoh C, Yokota T, Takahari D, Ura T and Muro K: Prognostic impact of the 6th and 7th American Joint Committee on Cancer TNM staging systems on esophageal cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys. 82:946–952. 2012. View Article : Google Scholar : PubMed/NCBI
25	Cheng Y, Li K, Diao D, Zhu K, Shi L, Zhang H, Yuan D, Guo Q, Wu X, Liu D and Dang C: Expression of KIAA0101 protein is associated with poor survival of esophageal cancer patients and resistance to cisplatin treatment in vitro. Lab Invest. 93:1276–1287. 2013. View Article : Google Scholar : PubMed/NCBI
26	Burrin JM and Price CP: Performance of three enzymic methods for filter paper glucose determination. Ann Clin Biochem. 21:411–416. 1984. View Article : Google Scholar : PubMed/NCBI
27	Cheng Y, Diao D, Zhang H, Guo Q, Wu X, Song Y and Dang C: High glucose-induced resistance to 5-fluorouracil in pancreatic cancer cells alleviated by 2-deoxy-D-glucose. Biomed Rep. 2:188–192. 2014. View Article : Google Scholar : PubMed/NCBI
28	Wichers MC and Maes M: The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci. 29:11–17. 2004.PubMed/NCBI
29	Kohl C and Sperner-Unterweger B: IDO and clinical conditions associated with depressive symptoms. Curr Drug Metab. 8:283–287. 2007. View Article : Google Scholar : PubMed/NCBI
30	Zheng ST, Zhang CS, Qin X, Gen YH, Liu T, Sheyhidin I and Lu XM: The status of phosphorylated p38 in esophageal squamous cell carcinoma. Mol Biol Rep. 39:5315–5321. 2012. View Article : Google Scholar : PubMed/NCBI
31	Pal A, Huang W, Li X, Toy KA, Nikolovska-Coleska Z and Kleer CG: CCN6 modulates BMP signaling via the Smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer. Cancer Res. 72:4818–4828. 2012. View Article : Google Scholar : PubMed/NCBI
32	Yu JP, Sun SP, Sun ZQ, Ni XC, Wang J, Li Y, Hu LJ and Li DQ: Clinical trial of thalidomide combined with radiotherapy in patients with esophageal cancer. World J Gastroenterol. 20:5098–5103. 2014. View Article : Google Scholar : PubMed/NCBI
33	Sun YR, Wang XY, Li SS, Dong HY and Zhang XJ: β-asarone from Acorus gramineus alleviates depression by modulating MKP-1. Genet Mol Res. 14:4495–4504. 2015. View Article : Google Scholar : PubMed/NCBI
34	Cuijpers P and Cristea IA: What if a placebo effect explained all the activity of depression treatments? World Psychiatry. 14:310–311. 2015. View Article : Google Scholar : PubMed/NCBI