The Expression And Significance Of Ion Channels And Receptors Related To Pacemaking Of ICC In Human Gastrointestinal Stromal Tumors

Background and Objects:Gastrointestinal stromal tumors(GISTs)is the most common mesenchymal tumors in gastrointestinal(GI)tract,with an annual incidence of 6-20/million,accounting for 1%of all gastrointestinal tumors and 70%of GI mesenchymal tumors.Modern medicine defines GISTs as a primary gastrointestinal tumor,originating from interstitial cells of Cajal(ICCs)or stem cells to ICCs differentiation.GISTs have acquired c-kit gene mutation and express c-kit protein(CD117),with a set of characteristic histological features including spindle cell morphology and epithelioid cell morphology.As the origination of GISTs,ICCs are the GI pacemaker cells,and they are found widely in the wall of the GI tract where they form a network around the myenteric plexus.ICCs are responsible for pacing basic slow waves,regulating smooth muscle contraction and relaxation,mediating neurotransmitter transfer functions of GI motility.The mechanisms of basic electrical rhythm of ICCs are quite complicated,now mostly studies consider that a variety of ion channels and receptors participate in the formation of GI slow waves.Our study aimed to detect the expressions of IP3R1/2/3,Kv1.1/1.6,HERG,Cx37/40/43,DOG-1 and TRPC4/5/6/7 in human GISTs,and further study whether GISTs maintain the basic structure of ICCs related to the pacemaker of slow wave during their occurrence and development processes.Methods:The expression of IP3R1/2/3,Kv1.1/1.6,HERG,Cx37/40/43,DOG-1 and TRPC4/5/6/7 were detected by real-time PCR(RT-PCR)in human GISTs.The locations and expressions of IP3R2,IP3R3,Kv1.1,Kv1.6,HERG,Cx43 and DOG-1 were detected by immunohistochemical method(SABC)in human GISTs and leiomyoma,respectively.Image-pro plus 6.0 was used to determine the positive area and mean optical density(MOD)of IP3R2,IP3R3,Kv1.1,Kv1.6,HERG,Cx43 and DOG-1 in GISTs and leiomyoma.Statistical analysis was performed using SPSS 13.0 and P<0.05 was considered significant.Results:(1)RT-PCR show that IP3R1/2/3,Kv1.1/1.6,HERG,Cx37/40/43,DOG-1 and TRPC4/5/6/7 express in human GISTs.(2)The mRNA levels of IP3R2,IP3R3,Kv1.1,Kv1.6,HERG,Cx43 and DOG-1 in high-risk groups of GISTs were statistically significant lower than that in very-low-risk and low-risk groups(P<0.05);(3)Immunohistochmeistry showed that with the biological behaviour malignant potential grade of GISTs increased,the positive areas and MOD of IP3R2,IP3R3,Kv1.1,Kv1.6,HERG,Cx43 and DOG-1 decreased,and the expression levels of IP3R2,IP3R3,Kv1.1,Kv1.6,HERG,Cx43 and DOG-1 in high-risk groups of GISTs were significant lower than that in very-low-risk or low-risk groups(P<0.05).As the control groups,the expression levels of IP3R2,IP3R3,Kv1.1,Kv1.6,HERG,Cx43 and DOG-1 were significant lower than each groups of GISTs(P<0.05).Conclusions:(1)IP3R1/2/3,Kv1.1/1.6,HERG,Cx37/40/43,DOG-1 and TRPC4/5/6/7 express in human GISTs.(2)With the biological behaviour malignant potential grade of GISTs increased,the mRNA and protein levels of IP3R2,IP3R3,Kv1.1,Kv1.6,HERG,Cx43 and DOG-1 decreased.The expression of IP3R2,IP3R3,Kv1.1,Kv1.6,HERG,Cx43 and DOG-1 may be associated with the risk stratification of primary GIST.(3)GISTs maintained part of the structures of ICCs for basic electrical rhythm in gastrointestinal motility.