Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer

Xiong,Honggang; Yang,Yixin; Yang,Kai; Zhao,Dan; Tang,Hong; Ran,Xiongwen

doi:10.3892/ijo.2017.4180

Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer

Authors:
- Honggang Xiong
- Yixin Yang
- Kai Yang
- Dan Zhao
- Hong Tang
- Xiongwen Ran
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Affiliations: Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
Published online on: October 31, 2017 https://doi.org/10.3892/ijo.2017.4180
Pages: 279-287

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Abstract

Recent studies have demonstrated that abnormal expression of the clock gene PER2 is closely associated with the development of a variety of cancer types. However, the expression of PER2 in oral squamous cell carcinoma (OSCC), a common malignant tumor in humans, and its correlations with the clinicopathological parameters and survival time of OSCC patients and the altered expression of important tumor-related genes remain unclear. In the present study, we detected the mRNA and protein expression levels of PER2, PIK3CA, PTEN, P53, P14ARF and caspase‑8 in OSCC tissues and cancer-adjacent oral mucosa by reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The results showed that the PER2, PTEN, P53, P14ARF and caspase‑8 mRNA and protein expression levels in OSCC were significantly reduced compared with those in cancer-adjacent tissues. Additionally, the PIK3CA protein expression level was significantly increased in OSCC tissues, whereas the mRNA level was not. Decreased expression of PER2 was signiﬁcantly associated with advanced clinical stage and the presence of lymphatic metastasis in OSCC patients. Patients with PER2‑negative expression had a significantly shorter survival time than those with PER2‑positive expression. PER2 expression was negatively correlated with PIK3CA and P53 levels, and positively correlated with PTEN, P14ARF and caspase‑8 levels. In summary, the results of this study suggest that loss of PER2 expression is closely associated with the genesis and development of OSCC and that PER2 may be an important prognostic biomarker in OSCC. PER2 may serve an antitumor role via the P53/P14ARF, PIK3CA/AKT and caspase‑8 pathways.

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1	Dibner C, Schibler U and Albrecht U: The mammalian circadian timing system: Organization and coordination of central and peripheral clocks. Annu Rev Physiol. 72:517–549. 2010. View Article : Google Scholar : PubMed/NCBI
2	Welsh DK, Yoo SH, Liu AC, Takahashi JS and Kay SA: Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr Biol. 14:2289–2295. 2004. View Article : Google Scholar : PubMed/NCBI
3	Takahashi JS: Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet. 18:164–179. 2017. View Article : Google Scholar
4	Miller BH, McDearmon EL, Panda S, Hayes KR, Zhang J, Andrews JL, Antoch MP, Walker JR, Esser KA, Hogenesch JB, et al: Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc Natl Acad Sci USA. 104:3342–3347. 2007. View Article : Google Scholar : PubMed/NCBI
5	Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F and Okamura H: Control mechanism of the circadian clock for timing of cell division in vivo. Science. 302:255–259. 2003. View Article : Google Scholar : PubMed/NCBI
6	Zhu Z, Hua B, Shang Z, Yuan G, Xu L, Li E, Li X, Sun N, Yan Z, Qian R, et al: Altered clock and lipid metabolism-related genes in atherosclerotic mice kept with abnormal lighting condition. BioMed Res Int. 2016:54385892016. View Article : Google Scholar : PubMed/NCBI
7	Di Cara F and King-Jones K: The circadian clock is a key driver of steroid hormone production in Drosophila. Curr Biol. 26:2469–2477. 2016. View Article : Google Scholar : PubMed/NCBI
8	Li J, Terry EE, Fejer E, Gamba D, Hartmann N, Logsdon J, Michalski D, Rois LE, Scuderi MJ, Kunst M, et al: Achilles is a circadian clock-controlled gene that regulates immune function in Drosophila. Brain Behav Immun. 61:127–136. 2017. View Article : Google Scholar
9	Tao H, Li X, Qiu JF, Cui WZ, Sima YH and Xu SQ: Inhibition of expression of the circadian clock gene period causes metabolic abnormalities including repression of glycometabolism in Bombyx mori cells. Sci Rep. 7:462582017. View Article : Google Scholar : PubMed/NCBI
10	Vieira E, Ruano E, Figueroa AL, Aranda G, Momblan D, Carmona F, Gomis R, Vidal J and Hanzu FA: Altered clock gene expression in obese visceral adipose tissue is associated with metabolic syndrome. PLoS One. 9:e1116782014. View Article : Google Scholar : PubMed/NCBI
11	Akashi M, Matsumura R, Matsuo T, Kubo Y, Komoda H and Node K: Hypercholesterolemia causes circadian dysfunction: A potential risk factor for cardiovascular disease. EBioMedicine. 20:127–136. 2017. View Article : Google Scholar : PubMed/NCBI
12	Wood PA, Yang X and Hrushesky WJ: Clock genes and cancer. Integr Cancer Ther. 8:303–308. 2009. View Article : Google Scholar
13	Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC and Bradley A: The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature. 400:169–173. 1999. View Article : Google Scholar : PubMed/NCBI
14	Albrecht U, Bordon A, Schmutz I and Ripperger J: The multiple facets of Per2. Cold Spring Harb Symp Quant Biol. 72:95–104. 2007. View Article : Google Scholar
15	Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ and Fu YH: An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science. 291:1040–1043. 2001. View Article : Google Scholar : PubMed/NCBI
16	Fu L, Pelicano H, Liu J, Huang P and Lee C: The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell. 111:41–50. 2002. View Article : Google Scholar : PubMed/NCBI
17	Wood PA, Yang X, Taber A, Oh EY, Ansell C, Ayers SE, Al-Assaad Z, Carnevale K, Berger FG, Peña MM, et al: Period 2 mutation accelerates ApcMin/+ tumorigenesis. Mol Cancer Res. 6:1786–1793. 2008. View Article : Google Scholar : PubMed/NCBI
18	Zhao H, Zeng ZL, Yang J, Jin Y, Qiu MZ, Hu XY, Han J, Liu KY, Liao JW, Xu RH, et al: Prognostic relevance of Period1 (Per1) and Period2 (Per2) expression in human gastric cancer. Int J Clin Exp Pathol. 7:619–630. 2014.PubMed/NCBI
19	Lin YM, Chang JH, Yeh KT, Yang MY, Liu TC, Lin SF, Su WW and Chang JG: Disturbance of circadian gene expression in hepatocellular carcinoma. Mol Carcinog. 47:925–933. 2008. View Article : Google Scholar : PubMed/NCBI
20	Wang Y, Hua L, Lu C and Chen Z: Expression of circadian clock gene human Period2 (hPer2) in human colorectal carcinoma. World J Surg Oncol. 9:1662011. View Article : Google Scholar : PubMed/NCBI
21	Hsu CM, Lin SF, Lu CT, Lin PM and Yang MY: Altered expression of circadian clock genes in head and neck squamous cell carcinoma. Tumour Biol. 33:149–155. 2012. View Article : Google Scholar
22	Hua H, Wang Y, Wan C, Liu Y, Zhu B, Yang C, Wang X, Wang Z, Cornelissen-Guillaume G and Halberg F: Circadian gene mPer2 overexpression induces cancer cell apoptosis. Cancer Sci. 97:589–596. 2006. View Article : Google Scholar : PubMed/NCBI
23	Cheng AY, Zhang Y, Mei HJ, Fang S, Ji P, Yang J, Yu L and Guo WC: Construction of a plasmid for overexpression of human circadian gene period2 and its biological activity in osteosarcoma cells. Tumour Biol. 36:3735–3743. 2015. View Article : Google Scholar : PubMed/NCBI
24	Oda A, Katayose Y, Yabuuchi S, Yamamoto K, Mizuma M, Shirasou S, Onogawa T, Ohtsuka H, Yoshida H, Hayashi H, et al: Clock gene mouse period2 overexpression inhibits growth of human pancreatic cancer cells and has synergistic effect with cisplatin. Anticancer Res. 29:1201–1209. 2009.PubMed/NCBI
25	Wang Q, Ao Y, Yang K, Tang H and Chen D: Circadian clock gene Per2 plays an important role in cell proliferation, apoptosis and cell cycle progression in human oral squamous cell carcinoma. Oncol Rep. 35:3387–3394. 2016. View Article : Google Scholar : PubMed/NCBI
26	Su X, Chen D, Yang K, Zhao Q, Zhao D, Lv X and Ao Y: The circadian clock gene PER2 plays an important role in tumor suppression through regulating tumor-associated genes in human oral squamous cell carcinoma. Oncol Rep. 38:472–480. 2017. View Article : Google Scholar : PubMed/NCBI
27	Chi AC, Day TA and Neville BW: Oral cavity and oropharyngeal squamous cell carcinoma - an update. CA Cancer J Clin. 65:401–421. 2015. View Article : Google Scholar : PubMed/NCBI
28	Wan X, Li X, Yang J, Lv W, Wang Q, Chen Y and Li Y: Genetic association between PIK3CA gene and oral squamous cell carcinoma: A case control study conducted in Chongqing, China. Int J Clin Exp Pathol. 8:13360–13366. 2015.
29	Chen Y, Hou Q, Yan W, Luo J, Chen D, Liu Z, He S and Ding X: PIK3CA is critical for the proliferation, invasiveness, and drug resistance of human tongue carcinoma cells. Oncol Res. 19:563–571. 2011. View Article : Google Scholar : PubMed/NCBI
30	Jasphin SS, Desai D, Pandit S, Gonsalves NM, Nayak PB and Iype A: Immunohistochemical expression of phosphatase and tensin homolog in histologic gradings of oral squamous cell carcinoma. Contemp Clin Dent. 7:524–528. 2016. View Article : Google Scholar : PubMed/NCBI
31	Rahmani A, Alzohairy M, Babiker AY, Rizvi MA and Elkarimahmad HG: Clinicopathological significance of PTEN and bcl2 expressions in oral squamous cell carcinoma. Int J Clin Exp Pathol. 5:965–971. 2012.PubMed/NCBI
32	Mao C, Lu Y, Lai Q, Xia Y and Yang C: Expression of p53 gene in oral squamous cell carcinoma and its relation with clinical and pathological parameters and prognosis of patients. Chin Med Sci J. 10:199–203. 1995.PubMed/NCBI
33	Shintani S, Nakahara Y, Mihara M, Ueyama Y and Matsumura T: Inactivation of the p14(ARF), p15(INK4B) and p16(INK4A) genes is a frequent event in human oral squamous cell carcinomas. Oral Oncol. 37:498–504. 2001. View Article : Google Scholar : PubMed/NCBI
34	Elrod HA, Fan S, Muller S, Chen GZ, Pan L, Tighiouart M, Shin DM, Khuri FR and Sun SY: Analysis of death receptor 5 and caspase-8 expression in primary and metastatic head and neck squamous cell carcinoma and their prognostic impact. PLoS One. 5:e121782010. View Article : Google Scholar : PubMed/NCBI
35	Lin J and Zhu MH: Interactive pathway of ARF-mdm2-p53. Ai Zheng. 22:328–330. 2003.In Chinese. PubMed/NCBI
36	Liu J, Zhang C and Feng Z: Tumor suppressor p53 and its gain-of-function mutants in cancer. Acta Biochim Biophys Sin (Shanghai). 46:170–179. 2014. View Article : Google Scholar
37	Gröbe A, Hanken H, Al-Dam A, Cachovan G, Smeets R, Krohn A, Clauditz T, Grob T, Simon R, Sauter G, et al: P53 immunohistochemical expression does not correlate with clinical features in 207 carcinomas of the oral cavity and in the head and neck region. Clin Oral Investig. 18:211–217. 2014. View Article : Google Scholar
38	Friedrich RE, Giese M, Riethdorf S and Loning T: P53-mutation in smears of oral squamous cell carcinoma. Anticancer Res. 20D:4927–4930. 2000.
39	Takami H, Yoshida A, Fukushima S, Arita H, Matsushita Y, Nakamura T, Ohno M, Miyakita Y, Shibui S, Narita Y, et al: Revisiting TP53 mutations and immunohistochemistry - A comparative study in 157 diffuse gliomas. Brain Pathol. 25:256–265. 2015. View Article : Google Scholar
40	Lai K, Killingsworth MC and Lee CS: Gene of month: PIK3CA. J Clin Pathol. 68:253–257. 2015. View Article : Google Scholar : PubMed/NCBI
41	Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P and Pavletich NP: Crystal structure of the PTEN tumor suppressor: Implications for its phosphoinositide phosphatase activity and membrane association. Cell. 99:323–334. 1999. View Article : Google Scholar : PubMed/NCBI
42	Di Cristofano A and Pandolfi PP: The multiple roles of PTEN in tumor suppression. Cell. 100:387–390. 2000. View Article : Google Scholar : PubMed/NCBI
43	Chen B, Tan Y, Liang Y, Li Y, Chen L, Wu S, Xu W, Wang Y, Zhao W and Wu J: Per2 participates in AKT-mediated drug resistance in A549/DDP lung adenocarcinoma cells. Oncol Lett. 13:423–428. 2017.PubMed/NCBI
44	Wang Z, Li L and Wang Y: Effects of Per2 overexpression on growth inhibition and metastasis, and on MTA1, nm23-H1 and the autophagy-associated PI3K/PKB signaling pathway in nude mice xenograft models of ovarian cancer. Mol Med Rep. 13:4561–4568. 2016. View Article : Google Scholar : PubMed/NCBI
45	Fulda S: Caspase-8 in cancer biology and therapy. Cancer Lett. 281:128–133. 2009. View Article : Google Scholar
46	Wang X, Fu Z, Chen Y and Liu L: Fas expression is downregulated in gastric cancer. Mol Med Rep. 15:627–634. 2017. View Article : Google Scholar :