Deregulated expression of circadian clock genes in gastric cancer

Hu, Ming‐Luen; Yeh, Kun‐Tu; Lin, Pei; Hsu, Cheng‐Ming; Hsiao, Hui‐Hua; Liu, Yi-Chang; Lin, Hugo You-Hsien; Lin, Sheng-Fung; Yang, Mingyu

doi:10.1186/1471-230x-14-67

Cited by 74 publications

(54 citation statements)

References 44 publications

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“…CRY2 is linked to poor survival outcomes and its silencing could increase sensitivity to oxaliplatin (21). Upregulation of PER2 and CRY1 in gastric cancer and CRY1 in colorectal cancer correlate with more advanced disease states and lymph node metastasis (56,57). CLOCK expression is increased in high-grade glioma tissues and is required for glioma progression through modulation of NF-κB activity (58).…”

Section: Discussionmentioning

confidence: 99%

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

Lai

2019

Preprint

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The circadian clock governs a large variety of fundamentally important physiological processes in all three domains of life. Consequently, asynchrony in timekeeping mechanisms could give rise to cellular dysfunction underpinning many disease pathologies including human neoplasms. Yet, detailed pancancer evidence supporting this notion has been limited. In an integrated approach uniting genetic, transcriptomic and clinical data of 21 cancer types (n=18,484), we interrogated copy number and transcript profiles of 32 circadian clock genes to identify putative loss-of-function (Clock Loss ) and gainof-function (Clock Gain ) players. Kaplan-Meier, Cox regression and receiver operating characteristic analyses were employed to evaluate the prognostic significance of both gene sets. Clock Loss and Clock Gain were associated with tumoursuppressing and tumour-promoting roles respectively. Downregulation of Clock Loss genes resulted in significant higher mortality rates in five cancer cohorts (n=2,914): bladder (P=0.027), glioma (P<0.0001), pan-kidney (P=0.011), clear cell renal cell (P<0.0001) and stomach (P=0.0007). In contrast, patients with high expression of oncogenic Clock Gain genes had poorer survival outcomes (n=2,784): glioma (P<0.0001), pan-kidney (P=0.0034), clear cell renal cell (P=0.014), lung (P=0.046) and pancreas (P=0.0059). Both gene sets were independent of other clinicopathological features to permit further delineation of tumours within the same stage. Circadian reprogramming of tumour genomes resulted in activation of numerous oncogenic pathways including those associated with cancer stem cells, suggesting that the circadian clock may influence self-renewal mechanisms. Within the hypoxic tumour microenvironment, circadian dysregulation is exacerbated by tumour hypoxia in glioma, renal, lung and pancreatic cancers, resulting in additional death risks. Tumour suppressive Clock Loss genes were negatively correlated with hypoxia inducible factor-1A targets in glioma patients, providing a novel framework for investigating the hypoxia-clock signalling axis. Loss of timekeeping fidelity promotes tumour progression and influences clinical outcomes. Clock Loss and Clock Gain may offer novel druggable targets for improving patient prognosis. Both gene sets can be used for patient stratification in adjuvant chronotherapy treatment. Emerging interactions between the circadian clock and hypoxia may be harnessed to achieve therapeutic advantage using hypoxia-modifying compounds in combination with firstline treatments. circadian clock | hypoxia | oncogene | tumour suppressor | gain-of-function | loss-of-function | pan-cancer | glioma | renal cancer Correspondence: alvina.lai@ndm.ox.ac.uk

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Section: Discussionmentioning

confidence: 99%

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

Lai

2019

Preprint

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“…In this study, by retrieving relevant previous reports through the keywords "gastric cancer and RNA," we finally selected four cancer-related protein coding genes, which have been tested by different kinds of experiments. These four genes ("NOV," "KIT," "SP1," and "CLOCK") were considered as seeds in the RWR model [33][34][35][36]. The initial probability P 0 of each seed mRNA was set as 1/n (where n is the number of seed mRNAs), while other non-seed mRNAs were set as 0.…”

Section: Rwr To Prioritize Gc Related Lncrnasmentioning

confidence: 99%

A Novel LncRNA-miRNA-mRNA Triple Network Identifies LncRNA RP11-363E7.4 as An Important Regulator of miRNA and Gene Expression in Gastric Cancer

Wang

Zhao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Recent evidence has shown that some long non-coding RNAs (lncRNAs) play important roles in various biological processes. However, the regulatory mechanism of lncRNA in gastric cancer (GC) remains unclear. Methods: We reannotated the GC gene expression profile into a lncRNA-mRNA biphasic profile and integrated the microRNA target data to construct a global GC triple network. A further clustering and random walk with restart analyses was performed on the triple network from the level of topology analyses. Quantitative real-time PCR was used to determine expression of lncRNA RP11-363E7.4. Kaplan-Meier analyses was performed to evaluate the prognostic value of lncRNA RP11-363E7.4. Results: We constructed a gastric cancer lncRNA-miRNA-mRNA network (GCLMN) including six lncRNAs, 332 mRNAs, and 3,707 edges. For the shared lncRNA RP11-363E7.4, the interacting gene and microRNA functional enrichment studies implied that lncRNA RP11-363E7.4 might function as a new regulator in GC. The expression of lncRNA RP11-363E7.4 was downregulated compared with that of paracarcinoma tissues in five GC samples. High expression of lncRNA RP11-363E7.4 was found to be correlated to better overall survival (OS) for GC patients. Conclusions: This study focused on GC lncRNA-miRNA-mRNA regulatory networks, and found that lncRNA RP11-363E7.4 was a new GC risk lncRNA, which might provide novel insight into a better understanding of the pathogenesis of GC.

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“…PER2 is reduced in various types of cancer cells, including breast cancer, neck squamous cell carcinoma, prostate cancer, colorectal cancer, hepatocellular carcinoma, skin cancer, gastric cancer, and myeloid leukemia (1,10,14,(20)(21)(22)(23)(24)(25)(26). PER2 can regulate downstream plentiful cell cycle genes, such as CyclinA, CyclinB1, CyclinD1, CyclinE, p53, and C-myc (14,(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

The circadian clock gene PER2 plays an important role in tumor suppression through regulating tumor-associated genes in human oral squamous cell carcinoma

Chen

Yang

et al. 2017

Oncology Reports

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Abstract. Low expression of the clock gene PER2 is closely related to carcinogenesis and the development of cancer; however, the mechanism of the low expression of PER2 that led to cell malignant transformation remains unclear. This study used RNA interference (RNAi) technology to silence PER2 in SCC15 human oral squamous cell carcinoma (OSCC) cells. Then it was found that the ability of cancer cell proliferation, migration, and invasion were markedly increased (P<0.05), and the ability of cancer cell apoptosis and the number of cells in G1/G0 phase were markedly reduced (P<0.05) after PER2 knockdown. PER2 knockdown increased the expression of MDM2, MMP2, and VEGF mRNA (P<0.05), and decreased the expression of p53, Bax, and TIMP-2 mRNA (P<0.05). The in vivo experiments also proved that the tumorigenicity of SCC15 cells was significantly enhanced after PER2 silence (P<0.05). Overall, these results show that PER2 through the regulation of the numerous important downstream tumor-related genes, plays a major role in tumor suppression, and it may be a novel molecular target for cancer treatment.

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Deregulated expression of circadian clock genes in gastric cancer

Cited by 74 publications

References 44 publications

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

A Novel LncRNA-miRNA-mRNA Triple Network Identifies LncRNA RP11-363E7.4 as An Important Regulator of miRNA and Gene Expression in Gastric Cancer

The circadian clock gene PER2 plays an important role in tumor suppression through regulating tumor-associated genes in human oral squamous cell carcinoma

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