Tavano Francesca, Pazienza Valerio, Fontana Andrea, Burbaci Francesca Paola, Panebianco Concita, Saracino Chiara, Lombardi Lucia, De Bonis Antonio, di Mola Fabio Francesco, di Sebastiano Pierluigi, Piepoli Ada, Vinciguerra Manlio, Fracavilla Massimo, Giuliani Francesco, Rubino Rosa, Andriulli Angelo, Mazzoccoli Gianluigi
Division of Gastroenterology, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza" , San Giovanni Rotondo (FG) , Italy .
Chronobiol Int. 2015 May;32(4):497-512. doi: 10.3109/07420528.2014.1003351. Epub 2015 Mar 23.
Pancreatic cancer (PC), the fourth leading cause of cancer-related deaths, is characterized by high aggressiveness and resistance to chemotherapy. Pancreatic carcinogenesis is kept going by derangement of essential cell processes, such as proliferation, apoptosis, metabolism and autophagy, characterized by rhythmic variations with 24-h periodicity driven by the biological clock. We assessed the expression of the circadian genes ARNLT, ARNLT2, CLOCK, PER1, PER2, PER3, CRY1, CRY2 and the starvation-activated histone/protein deacetylase SIRT1 in 34 matched tumor and non-tumor tissue specimens of PC patients, and evaluated in PC derived cell lines if the modulation of SIRT1 expression through starvation could influence the temporal pattern of expression of the circadian genes. We found a significant down-regulation of ARNLT (p = 0.015), CRY1 (p = 0.013), CRY2 (p = 0.001), PER1 (p < 0.0001), PER2 (p < 0.001), PER3 (p = 0.001) and SIRT1 (p = 0.017) in PC specimens. PER3 and CRY2 expression levels were lower in patients with jaundice at diagnosis ( < 0.05). Having adjusted for age, adjuvant therapy and tumor stage, we evidenced that patients with higher PER2 and lower SIRT1 expression levels showed lower mortality (p = 0.028). Levels and temporal patterns of expression of many circadian genes and SIRT1 significantly changed upon serum starvation in vitro, with differences among four different PC cell lines examined (BXPC3, CFPAC, MIA-PaCa-2 and PANC-1). Serum deprivation induced changes of the overall mean level of the wave and amplitude, lengthened or shortened the cycle time and phase-advanced or phase-delayed the rhythmic oscillation depending on the gene and the PC cell line examined. In conclusion, a severe deregulation of expression of SIRT1 and circadian genes was evidenced in the cancer specimens of PC patients, and starvation influenced gene expression in PC cell lines, suggesting that the altered interplay between SIRT1 and the core circadian proteins could represent a crucial player in the process of pancreatic carcinogenesis.
胰腺癌（PC）是癌症相关死亡的第四大主要原因，其特点是具有高度侵袭性且对化疗耐药。胰腺癌的发生是由细胞基本过程的紊乱所驱动，如增殖、凋亡、代谢和自噬，这些过程具有由生物钟驱动的24小时周期性节律变化。我们评估了34例PC患者配对的肿瘤和非肿瘤组织标本中昼夜节律基因ARNLT、ARNLT2、CLOCK、PER1、PER2、PER3、CRY1、CRY2以及饥饿激活的组蛋白/蛋白质去乙酰化酶SIRT1的表达，并在PC衍生细胞系中评估通过饥饿调节SIRT1表达是否会影响昼夜节律基因的时间表达模式。我们发现PC标本中ARNLT（p = 0.015）、CRY1（p = 0.013）、CRY2（p = 0.001）、PER1（p < 0.0001）、PER2（p < 0.001）、PER3（p = 0.001）和SIRT1（p = 0.017）显著下调。诊断时伴有黄疸的患者中PER3和CRY2表达水平较低（< 0.05）。在调整年龄、辅助治疗和肿瘤分期后，我们证明PER2表达较高且SIRT1表达较低的患者死亡率较低（p = 0.028）。在体外血清饥饿时，许多昼夜节律基因和SIRT1的表达水平及时间模式发生显著变化，在所检测的四种不同PC细胞系（BXPC3、CFPAC、MIA-PaCa-2和PANC-1）之间存在差异。血清剥夺诱导了波的总体平均水平和振幅的变化，延长或缩短了周期时间，并根据所检测的基因和PC细胞系使节律振荡提前或延迟。总之，在PC患者的癌症标本中证实了SIRT1和昼夜节律基因表达的严重失调，饥饿影响了PC细胞系中的基因表达，这表明SIRT1与核心昼夜节律蛋白之间改变的相互作用可能是胰腺癌发生过程中的关键因素。
