The Regulation of Cyclins and Cyclin-Dependent Kinases in the Development of Gastric Cancer

Abstract

Gastric cancer predominantly occurs in adenocarcinoma form and is characterized by uncontrolled growth and metastases of gastric epithelial cells. The growth of gastric cells is regulated by the action of several major cell cycle regulators including Cyclins and Cyclin-dependent kinases (CDKs), which act sequentially to modulate the life cycle of a living cell. It has been reported that inadequate or over-activity of these molecules leads to disturbances in cell cycle dynamics, which consequently results in gastric cancer development. Manny studies have reported the key roles of Cyclins and CDKs in the development and progression of the disease in either in vitro cell culture studies or in vivo models. We aimed to compile the evidence of molecules acting as regulators of both Cyclins and CDKs, i.e., upstream regulators either activating or inhibiting Cyclins and CDKs. The review entails an introduction to gastric cancer, along with an overview of the involvement of cell cycle regulation and focused on the regulation of various Cyclins and CDKs in gastric cancer. It can act as an extensive resource for developing new hypotheses for future studies.

Keywords: Cyclin-dependent kinases (CDKs); Cyclins; cell cycle regulation; cell signaling; gastric cancer; kinases; molecular oncology.

Figure 1

General pathway of cell cycle regulation. Various Cyclins activate different CDKs sequentially to progress the cell cycle and determine the fate of the cells. The CDKs in turn act to phosphorylate various substrates for transitioning the cell cycle phases. For example, RB is one of the major regulators of the cell cycle, and is the target of CDK4/6, CDK2, and CDK1, and together with activated E2F and its target genes, leads to the transition of cell cycle phases.

Figure 2

Overview of cell cycle regulation with respect to CDKs and their major regulators. The upstream factors of Cyclins and CDKs can either activate or downregulate their respective functions and cause the cell cycle to halt at various time points including the G1 restriction point, G1/S checkpoint, G2/M checkpoint, and Spindle Assembly Checkpoint (SAC). The description of these factors and their action on Cyclins and CDKs are detailed in the main text.

Figure 3

Cyclin D1 regulation in gastric cancer progression. Cyclin D1 levels are upregulated in gastric cancer and are affected positively (green arrows) for the oncogenic transformation of gastric cells via the action of upstream factors (blue). In normal gastric cells, the levels of Cyclin D1 remain tightly controlled via the negative regulators (red lines), which directly inhibit the transcription of the Cyclin D1 gene or inhibit the binding of Cyclin D1 with CDK4/6 directly or indirectly. The modes of action of these regulators are described in the main text.

Figure 4

CDK4/6 regulation in gastric cancer progression. CDK4/6 are kinases that accelerate the cell cycle progression from the G1 phase. Different long non-coding RNAs (green) facilitate the upregulation of these CDKs via sponging (red lines) microRNAs (orange). Moreover, other pathways such as PI3K-Akt and Hippo function in activating (green arrows) the CDK4/6 for developing gastric cancer. The negative upstream regulators of CDK4/6, such as CDC37L1 and AKT, are shown in grey and keep the levels of CDK4/6 down in gastric cells. The overall mechanisms for the regulation of CDK4/6 in the gastric cells are explained in the main text.

Figure 5

Cyclin E1 regulation in gastric cancer progression. Cyclin E functions to progress cells from G1 to the S phase and remains upregulated in the S phase. In gastric tumors, Cyclin E1 expression is higher than in normal tissues. The factors activating the functions of Cyclin E in gastric cells are shown, with green arrows indicating activation and red lines showing inhibition. The mechanisms of these regulators are described in detail in the main text.

Figure 6

CDK2 regulation in gastric cancer progression. CDK2 is the major driver of the S phase in the cell cycle and promotes various pathways. Positive regulators (green arrows) including long non-coding RNAs (green) and negative regulators of CDK2 (red lines), including micro-RNAs (orange), are shown. The details of the mode of action of these molecules on CDK2 are explained in the text.

Figure 7

Cyclin B1/CDK1 regulation in gastric cancer progression. The Cyclin B1/CDK1 axis is at the critical conjuncture of G2-M transition and mitotic exit, and is therefore an important component of the cell division pathway. Various factors, including long non-coding RNAs (green), among others (green arrows), activate this axis and are involved in the progression of gastric cancer. The two miRNAs (orange), however, negatively affect the Cyclin B1 and CDK1 in gastric cells, inhibiting their functions and oncogenic properties. Further details of the regulating factors affecting the Cyclin B1/CDK1 axis are described in the main text.