Correlation between the expressions of gastrin, somatostatin and cyclin and cyclin-depend kinase in colorectal cancer

AIM: To explore the correlation between the expressions of gastrin (GAS), somatostatin (SS) and cyclin, cyclindependent kinase (CDK) in colorectal cancer, and to detect the specific regulatory sites where gastrointestinal hormone regulates cell proliferation.METHODS: Seventy-nine resected large intestine carcinomatous specimens were randomly selected.Immunohistochemical staining for GAS, SS, cyclin D1, cyclin E, cyclin A, cyclin B1, CDK2 and CDK4 was performed according to the standard streptavidinbiotin-peroxidase (S-P) method. According to the semiquantitative integral evaluation, SS and GAS were divided into high, middle and low groups. Cyclin D1, cyclin E,cyclin A, cyclin B1, CDK2, CDK4 expressions in the three GAS and SS groups were assessed.RESULTS: The positive expression rate of cyclin D1 was significantly higher in high (78.6%, 11/14) and middle GAS groups (73.9%, 17/23) than in low GAS group (45.2%, 19/42) (P＜0.05,χ2 high vs low = 4.691; P＜0.05, χ2 middle vs low =4.945). The positive expression rate of cyclin A was significantly higher in high (100%, 14/14)and middle GAS groups (82.6%, 19/23) than in low GAS group (54.8%, 23/42) (P＜0.01, χ2 high vs low = 9.586;P＜0.05, χ middle vs low = 5.040). The positive expression rate of CDK2 was significantly higher in high (92.9%, 13/14)and middle GAS groups (87.0%, 20/23) than in low GAS group (50.0%, 21/42) (P＜0.01, χ2 high vs low = 8.086;P＜0.01, χ2 middle vs low = 8.715). The positive expression rate of CDK4 was significantly higher in high (78.6%, 11/14)and middle GAS groups (78.3%, 18/23) than in low GAS group (42.9%, 18/42) (P＜0.05, χ2 high vs low = 5.364;P＜0.01, χ2 middle vs low = 7.539). The positive expression rate of cyclin E was prominently higher in low SS group (53.3%, 24/45) than in high (9.1%, 1/11) and middle (21.7%, 5/23) SS groups (P＜0.05, χ2 high vs low = 5.325;P＜0.05, χ2 middle vs low = 6.212). The positive expression rate of CDK2 was significantly higher in low SS group (77.8%, 35/45) than in high SS group (27.3%, 3/11)(P＜0.01, χ2 high vs low = 8.151). There was a significant positive correlation between the integral ratio of GAS to SS and the semi-quantitative integral of cyclin D1, cyclin E, cyclin A, CDK2, CDK4 (P＜0.05, D1rs = 0.252; P＜0.01,Ers = 0.387; P＜0.01, Ars = 0.466; P＜0.01, K2rs = 0.519;P＜0.01, K4rs = 0.434).CONCLUSION: The regulation and control of gastrin, SS in colorectal cancer cell growth may be directly related to the abnormal expressions of cyclins D1, A, E, and CDK2,CDK4. The regulatory site of GAS in the cell cycle of colorectal carcinoma may be at the G1, S and G2 phases.The regulatory site of SS may be at the entrance of S phase.

Depletion of telomerase RNA inhibits growth of gastrointestinal tumors transplanted in mice

AIM: To explore effects of telomerase RNA-targeting phosphorothioate antisense oligodeoxynucleotides (PS-ASODN) on growth of human gastrointestinal stromal tumors transplanted in mice. METHODS: A SCID mouse model for transplantation of human gastrointestinal stromal tumors (GISTs) was established using tumor cells from a patient who was diagnosed with GIST and consequently had been treated with imatinib. GIST cells cultured for 10 passages were used for inoculation into mice. Transfection of PS-ASODN was carried out with Lipotap Liposomal Transfection Reagent. GISTs that subsequently developed in SCID mice were subjected to intratumoral injection once daily from day 7 to day 28 postinoculation, and mice were divided into the following four groups according to treatment: PS-ASODN group (5.00 μmoL/L of oligonucleotide, each mouse received 0.2 mL once daily); imatinib group (0.1 mg/g body weight); liposome negative control group (0.01 mL/g); and saline group (0.01 mL/g). On day 28, the mice were sacrificed, and tumor attributes including weight and longest and shortest diameters were measured. Tumor growth was compared between treatment groups, and telomerase activity was measured by enzyme-linked immunosorbent assay. Apoptosis was examined by flow cytometry. Real-time polymerase chain reaction was used to detect expression of the mRNA encoding the apoptosis inhibition B-cell leukemia/lymphoma 2 (bcl-2 ) gene. RESULTS: In the PS-ASODN group, tumor growth was inhibited by 59.437%, which was markedly higher than in the imatinib group (11.071%) and liposome negative control group (2.759%) [tumor inhibition=(mean tumor weight of control group - mean tumor weight of treatment group)/(mean tumor weight of control group) × 100%]. Telomerase activity was significantly lower (P < 0.01) in the PS-ASODN group (0.689 ± 0.158) compared with the imatinib group (1.838 ± 0.241), liposome negative control group (2.013 ± 0.273), and saline group (2.004 ± 0.163). Flow cytometry revealed that the apoptosis rate of tumor cells treated with PS-ASODN was 20.751% ± 0.789%, which was higher (P < 0.01) than that of the imatinib group (1.163% ± 0.469%), liposome negative control group (1.212% ± 0.310%), and saline group (1.172% ± 0.403%). Expression of bcl-2 mRNA in the transplanted GISTs was markedly downregulated (P < 0.01) in the PS-ASODN group (7.245 ± 0.739) compared with the imatinib group (14.153 ± 1.618) and liposome negative control group (16.396 ± 1.351).CONCLUSION: PS-ASODN can repress GIST growth, mediated perhaps by inhibition of telomerase activity and downregulation of bcl-2 expression.