Circadian gene hClock enhances proliferation and inhibits apoptosis of human colorectal carcinoma cells in vitro and in vivo

Abstract

Colorectal carcinoma (CRC) is one of the most prevalent types of malignancy-associated mortality worldwide. Previous studies have demonstrated that amplification and overexpression of the human circadian locomotor output cycles kaput gene (hClock) was closely associated with a high risk for CRC as well as poor prognosis in CRC patients. However, the underlying molecular mechanisms of CRC remain to be fully elucidated. In the present study, hClock was exogenously overexpressed in the CRC cell line SW480 via infection of a lentivirus vector expressing hClock; in addition, a lentivirus vector-based RNA interference approach, using short hairpin RNA, was performed in order to knockdown hClock in SW620 cells. The results showed that upregulation of hClock promoted proliferation and inhibited apoptosis in SW480 cells in vitro and in vivo, while downregulation of hClock inhibited SW620 cell proliferation and accelerated apoptosis in vitro. Upregulation of hClock enhanced the activity of the anti-apoptotic gene phosphorpylated (p-) AKT and inhibited the expression of the pro-apoptotic gene B cell lymphoma-2 (Bcl-2)-associated X protein and Bcl-2 homology 3 interacting domain death agonist. Furthermore, targeted inhibition of hClock activity reduced p-AKT expression. In conclusion, the results of the present study suggested that the circadian gene hClock promoted CRC progression and inhibit tumor cell apoptosis in vitro and in vivo, while silencing hClock was able to reverse this effect.

Circadian Clock, Cell Division, and Cancer: From Molecules to Organism

“…For instance, human colorectal cancers often show higher expression of Clock or Bmal1 genes compared to healthy tissue [112,113,114]. In agreement with this, overexpression of CLOCK increases proliferation of colorectal carcinoma cells in vitro and in vivo [115]. Another study reports elevated levels of CLOCK in ERα-positive breast tumor samples.…”

Cancer and the Circadian Clock

“…Furthermore, upstream regulators may play a role in modulating tumor-suppressive potential of CLOCK and BMAL1, as studies have shown that the unfolded protein response induces a phase shift in circadian oscillations via direct regulation of miR-211 to suppress Clock and Bmal1 expression impacting tumor progression (32). While these preliminary studies indicate that Clock and BMAL1 may serve tumor suppressor-like functions, exceptions exist in colorectal cancer, wherein Clock and Bmal1 expression is elevated, and modeling studies linked high CLOCK expression to increased proliferation (33,34). In addition, in acute myeloid leukemia (AML), Clock and Bmal1 are required for growth of AML (35).…”

CLOCK Promotes Endothelial Damage by Inducing Autophagy through Reactive Oxygen Species

“…We found that Tiron could effetely suppress cell autophagy and restore cell viability. It has been shown that CLOCK was found to be significantly increased in gliomas and colorectal carcinoma [32, 33]. ROS levels were also increased in many cancers.…”