The role of circadian clock genes in tumors

Figures & data

Figure 1 Mammalian circadian clock network. BMAL1 proteins combine with CLOCK or NPAS2 to generate BMAL1:CLOCK or BMAL1:NPAS2 heterodimers, which cause transcriptional activation of core clock genes (for example, Per, Cry, and Dec) via a combination of E-box elements; this in turn inhibits BMAL1:CLOCK/NPAS2 dimer activity. Meanwhile, the BMAL1:CLOCK/NPAS2 dimers activate the transcription of the Rev-erbα and Rorα genes, and the resulting translated proteins promote and inhibit the transcription of Bmal1, respectively.

Abbreviations: Bmal1/BMAL1, Brain and muscle Aarnt-like protein 1; Clock/CLock, Circadian locomotor output cycles kaput k; Cry/CRY, Cryptochrome; Dec/DEC, Differentiated embryo-chondrocyte expressed; Npas2/NPAS2, Neuronal PAS domain protein 2; Per/PER, Period; Rev-erb, nuclear receptor subfamily; ROR, retinoid-related orphan receptor; RRE, ROR elements.

Table 1 Clock genes in oral cancer

Ref.	Cell type/origin	Methods	Results
Sato et al^61	CA9-22 cell line; human gingival cancer tissue and noncancerous tissue from 13 patients	Knockdown and overexpression of PER1 and PER3; RT-qPCR; western blotting	PER1 knockdown enhanced apoptosis, while PER3 knockdown inhibited apoptosis in CA9-22 cells induced by CDDP treatment; PER1 overrepresented in cancerous tissue; PER3 overrepresented in noncancerous tissue
Hsu et al^129	Human cancerous and noncancerous tissue from 40 HNSCC patients	RT-qPCR	PER1, PER2, PER3, CRY1, CRY2, BMAL1, and CKIε were significantly downregulated; downregulated PER3, CRY2, and BMAL1 expression was correlated with more advanced cancer stages, while downregulated PER3 correlated with larger tumor size, deeper tumor invasion, and poor survival
Chen et al^152	Human cancerous and healthy adjacent tissue from 41 OSCC patients	Immunocytochemistry; RT-qPCR	Decreased expression of PER1 mRNA and protein in cancerous tissues; gradually decreased expression during cancer development
Zhao et al^150	32 mice injected with human OSCC cell line BcaCD885	Nude mouse model of OSCC	Circadian rhythm in tumor volume and proliferative index, not in apoptotic index
Hsu et al^151	PB leukocytes from 94 patients with HNSCC and 56 healthy individuals	RT-qPCR; immunocytochemistry	9 CCGs were significantly downregulated in PB leukocytes of patients with HNSCC; PER1 and CLOCK expression in PB leukocytes can be a marker for prognosis evaluation during postoperative follow-up in patients with HNSCC
Ye et al^114	Dimethylbenzanthracene-induced cancer, precancerous lesions, and normal tissues from 90 Syrian golden hamsters	RT-qPCR	Variations in the daily rhythm characteristics of the clock genes PER1, C-MYC, and P53 correlate with the development of cancer
Tan et al^53	Dimethylbenzanthracene-induced cancer, precancerous lesions, and normal tissues from 90 Syrian golden hamsters	RT-qPCR	Variations in the daily rhythm characteristics of the clock genes PER2, P53, Cyclin D1, CDK1, and Cyclin B1 correlate with the development of cancer
Fu et al^170	SCC15 cell line nude mice	PER1 knockdown; RT-qPCR; flow cytometry assay; in vivo tumorigenesis assay	Increased expression of Cyclin D1, Cyclin E, Cyclin B1, CDK1, and WEE1; decreased expression of P53, Cyclin A2, P16, P21, and CDC25; fewer cells in S phase and more cells in G2/M phase; enhanced proliferation and reduced apoptosis; enhanced tumorigenicity in vivo
Li et al^71	SCC15 cell line nude mice	PER1 knockdown; RT-qPCR; western blotting; colony formation; flow cytometry assay; cell migration/ invasion assay; in vivo tumorigenesis assay	Increased mRNA levels of Ki-67, Mdm2, Bcl-2, Mmp2, and Mmp9; decreased c-Myc, p53, Bax, and Timp-2; proliferation, migration, and invasion increased whereas apoptosis decreased; enhanced in vivo tumerogenesis
Wang et al^80	Tca8113 cell line	Per2 downregulation; RT-qPCR	Increased Cyclin A2, B1, and D1, CDK4, CDK6, and E2F1; decreased p53, p16, and p21; increased profileration; decreased apoptosis
Su et al^153	SCC15 cell line nude mice	PER2 knockdown; RT-qPCR; in vivo tumorigenesis assay	Cell proliferation, migration, and invasion markedly increased, while cancer cell apoptosis and number of cells in the G1/G0 phase reduced; enhanced in vivo tumerogenesis
Tang et al^154	53 cases of TSCC tissue and adjacent noncancerous tissue specimens; 50 cases of normal tongue tissue specimens; human TSCC cell lines (SCC9, SCC25, CAL27)	Knockdown and overexpression of Bmal1; chromatin immunoprecipitation assay; xenografted tumor model; western blotting	Bmal1 expression was downregulated and its rhythmic pattern of expression was affected in TSCC samples and cell lines; Bmal1 inhibited cell proliferation, migration, and invasion in vitro and tumor growth in vivo; Bmal1 inhibited tumorigenesis and increased paclitaxel sensitivity, and its chronotherapy efficacy was correlated with fluctuations of Bmal1 mRNA level
Xiong et al^86	OSCC tissues and cancer-adjacent tissues from 8 patients; paraffin-embedded tissue sections of 40 OSCC patients	RT-qPCR; western blotting; immunohistochemistry	PER2, PTEN, P53, P14ARF, and Caspase-8 mRNA and protein expression levels in OSCC were significantly downregulated; reduced PER2 promoted the occurrence and metastasis of OSCC, and shortened the survival time; PER2 expression was negatively correlated with PIK3CA and P53 levels, and positively correlated with PTEN, P14ARF, and Caspase-8 levels

Abbreviations: BMAL1, Brain and muscle Aarnt-like protein 1; CCG, clock-controlled gene; CDK, cyclin-dependent kinase; CK1ε, Casein kinase 1ε; CLOCK, Circadian locomotor output cycles kaput k; CRY, Cryptochrome; HNSCC, head and neck squamous cell carcinoma; Mdm2, Murine double minute 2; OSCC, oral squamous cell carcinoma; PB, peripheral blood; PER, Period; RT-qPCR, quantitative reverse transcription polymerase chain reaction.