Study On The Protective Mechanism Of Vitamin D On Colorectal Cancer

Colorectal cancer is one of the most familiar cancers in the world, the mortality is thethird of all cancers all over the world. The latest data from the Chinese Ministry of Healthshow that the mortality of colorectal cancer is the fifth of all cancers in China and themortality is also increasing year after year. The mortality and disease burden of colorectalcancer will be reduced if available measurement which is focus on etiology could be taken.But, the pathogeny of colorectal cancer has still not been illustrated.Many studies showed, vitamin D may be a protective factor of colorectal cancer, butthe results were not consistent. Now the researchers think the protective function ofvitamin D may contain the following items: depress cellular proliferation, promote cellulardifferentiation and induce cellular adoptosis. Whereas the certain mechanism has not beenclear yet. So detect the protective mechanism of vitamin D can help us clarify therelationship between vitamin D and colorectal cancer, which is very important for us tomake prevent strategy and measurement for colorectal cancer.Nowadays, according to many researches, vitamin D and its analog may induce BMP(Bone morpuogenetic protein) and then act the BMP-Smad signal pathway, inactive ofBMP-Smad signal pathway is related to the occurrence of colorectal cancer. So we canpresume vitamin D may reduce the risk for colorectal cancer through keeping theBMP-Smad signal pathway normal.Furthermore, relative studies showed, in humans, vitamin D metabolism needcytochrome P450, contained CYP2R1, CYP24A1and CYP27B1. And they tie up vitaminD metabolism. CYP2R1gene mutation can lead to25(OH)vitaminD3deficiency,CYP24A1and CYP27B1gene dolymorphism is related to the occurrence of colorectalcancer. So we presume CYP2R1gene mutation may be important in the relationshipbetween vitamin D and colorectal cancer.Hence, our study will make the following studies to make sure the above hypothesis. Part1. The function of BMP-Smad signal pathway in the relationship betweenvitamin D and colorectal cancerAims: Detect the function of BMP-Smad signal pathway in the relationship betweenvitamin D and colorectal cancer.Methods: We adopt the case-case-control study. The cases contained colorectal cancerpatients who will accept operation, the controls contained healthy people who come to domedical examination in Changhai hospital. We use electrochemiluminsecence (ECL) toexam serum25(OH) vitamin D3level of cases and controls, and useimmunohistochemistry (IHC) to test five factors (BMPR1,2,Smad1,5,8and Smad4)ofBMP-Smad signal pathway of cases. And then we use single factor and multifactoranalysis to compare the difference of serum25(OH)vitamin D3level through BMP-Smadsignal pathway (+) cases, BMP-Smad signal pathway (-) and controls. And then detect thefunction of BMP-Smad signal pathway in the relationship between vitamin D andcolorectal cancer. Single factor analysis contained X2test or T test, multi-factor analysis ismainly multi-Logistic regression analysis.Results: Finally, we brought122colorectal adenocarcinoma into case group, and128healthy people into control group. Between these two groups, the difference of age andgender were not significant.1. Relationship between vitamin D and CRC.According to single factor analysis, serum25(OH) vitamin D3, fruits, milk, coffee andwhite meat(containing chicken, dunk and fish) were potential protective factors ofcolorectal cancer(P＜0.25), smoking, drinking, surgery of non-intestinal diseases and redmeat(containing pork, beef and lamb) were potential risk factors of colorectal cancer(P＜0.25).Multi-factor analysis showed that, serum25(OH)vitamin D3, milk, and white meatwere protective factors of colorectal cancer(P<0.05), the ORs (95%CI) were respectively 0.12(0.05,0.28)(the highest vitamin D level compare to the lowest vitamin D level),0.43(0.22,0.84),0.40(0.21,0.78), drinking, surgery of non-intestinal diseases and red meatwere risk factors of colorectal cancer(P<0.05), the ORs (95%CI) were5.57(2.51,12.34),1.96(0.99,3.87),2.35(1.24,4.48) respectively2. Relationship through vitamin D, BMPR1A and CRCMulti-factor analysis of BMPR1A(+) case group and control showed, serum25(OH)vitamin D3is a protective factor of BMPR1A(+) colorectal cancer (P_trend=0.002), theOR(95%CI) was0.21(0.08,0.59)(the highest vitamin D level compare to the lowestvitamin D level).Multi-factor analysis of BMPR1A(-) case group and control showed, serum25(OH)vitamin D3is a protective factor of BMPR1A(-) colorectal cancer (P_trend<0.001), theOR(95%CI) was0.03(0.01,0.15)(the highest vitamin D level compare to the lowestvitamin D level).Multi-factor analysis of BMPR1A(+) case group and BMPR1A(-) case group showed,the difference of vitamin D between BMPR1A(+) case group and BMPR1A(-) case groupwas not significant(P_trend=0.054).Above all, the results indicated vitamin D was a protective factor of colorectal cancer,and this was independent of BMPR1A.3. Relationship through vitamin D, BMPR1B and CRCMulti-factor analysis of BMPR1B (+) case group and control group showed, serum25(OH) vitamin D3is a protective factor of BMPR1B (+) colorectal cancer (P_trend<0.001),the OR(95%CI) was0.09(0.03,0.25)(the highest vitamin D level compare to the lowestvitamin D level).Multi-factor analysis of BMPR1B (-) case group and control group showed, serum25(OH) vitamin D3is a protective factor of BMPR1B (-) colorectal cancer (P_trend=0.007),the OR(95%CI) was0.15(0.04,0.65)(the highest vitamin D level compare to the lowest vitamin D level).Multi-factor analysis of BMPR1B (+) case group and BMPR1B (-) case group showed,the difference of vitamin D between BMPR1B (+) case group and BMPR1B (-) case groupwas not significant (P_trend=0.293).So, the results indicated vitamin D was a protective factor of colorectal cancer, and theprotective function was independent of BMPR1B.4. Relationship through vitamin D, BMPR2and CRCMulti-factor analysis of BMPR2(+) case group and control group showed, serum25(OH)vitamin D3is protective factor of BMPR2(+) colorectal cancer (P_trend<0.001), theOR(95%CI) was0.04(0.01,0.16)(the highest vitamin D level compare to the lowestvitamin D level).Multi-factor analysis of BMPR2(-) case group and control group showed, serum25(OH)vitamin D3is a protective factor of BMPR2(-) colorectal cancer (P_trend=0.006), the OR(95%CI) was0.24(0.08,0.72)(the highest vitamin D level comPare to the lowest vitaminD level).Multi-factor analysis of BMPR2(+) case group and BMPR2(-) case group showed,serum25(OH)vitamin D3level was related to the state of BMPR2in colorectal cancer(P_trend=0.008), the OR (95%CI) was0.10(0.02,0.56),(the highest vitamin D level compareto the lowest vitamin D level).According to above results, we found there was relation between serum vitamin D leveland BMPR2state in colorectal cancer, the protective function of vitamin D on colorectalcancer was stronger in BMPR2(+) case group than in BMPR2(-) case group.5. Relationship through vitamin D, pSmad1/5/8and CRCMulti-factor analysis of pSmad1/5/8(+) case group and control group showed, serum25(OH)vitamin D3is a protective factor of pSmad1/5/8(+) colorectal cancer (P_trend=0.002),the OR(95%CI) was0.03(0.02,0.35)(the highest vitamin D level compare to the lowest vitamin D level).Multi-factor analysis of pSmad1/5/8(-) case group and control group showed, serum25(OH)vitamin D3is a protective factor of pSmad1/5/8(+) colorectal cancer (Ptrend<0.001),the OR(95%CI) was0.12(0.50,0.29)(the highest vitamin D level compare to the lowestvitamin D level).Multi-factor analysis of pSmad1/5/8(+) case group and pSmad1/5/8(-) case groupshowed, the difference of serum25(OH)vitamin D3level between pSmad1/5/8(+) casegroup and pSmad1/5/8(-) case group was not significant (Ptrend=0.687).According to these results, we found vitamin D was a protective factor of colorectalcancer, and this protective function was independent of pSmad1/5/8.6. Relationship through vitamin D, Smad4and CRCMulti-factor analysis of Smad4(+) case group and control group showed, serum25(OH)vitamin D3is a protective factor of Smad4(+) colorectal cancer(Ptrend<0.001), theOR(95%CI) was0.07(0.02,0.27)(the highest vitamin D level compare to the lowestvitamin D level).Multi-factor analysis of Smad4(-) case group and control group showed, serum25(OH)vitamin D3is a protective factor of Smad4(-) colorectal cancer (Ptrend<0.001), theOR(95%CI) was0.09(0.03,0.28)(the highest vitamin D level compare to the lowestvitamin D level).Multi-factor analysis of Smad4(+) case group and Smad4(-) case group showed, thedifference of serum25(OH)vitamin D3level between Smad4(+) case group and Smad4(-)case group was not significant (Ptrend=0.131).Hence, it is indicated that vitamin D was a protective factor of colorectal cancer, and thiswas independent of Smad4.Conclusion: There was relation between serum vitamin D level and BMPR2state incolorectal cancer, the protective function of vitamin D on colorectal cancer was stronger in BMPR2(+) case group than in BMPR2(-) case group. And the protective function wasindependent of BMPR1A, BMPR1B, pSmad1/5/8and Smad4state in colorectal cancer.Part2. The function of CYP2R1in the relationship between vitamin D and colorectalcancerAims: Detect the function of CYP2R1in the relationship between vitamin D andcolorectal cancer.Methods: We adopt the case-case-control study. The cases contained colorectal cancerpatients who will accept operation, the controls contained healthy people who come to domedical examination in Changhai hospital. We use electrochemiluminsecence (ECL) toexam serum25(OH)vitamin D3level of cases and controls, and use immunohistochemistry(IHC) to test CYP2R1of cases. And then we use single factor and multifactor analysis tocompare the difference of serum25(OH)vitamin D3level through CYP2R1(-) cases,CYP2R1(+) cases and controls. And then detect the function of CYP2R1in therelationship between vitamin D and colorectal cancer. Single factor analysis contained X2test or T test, multi-factor analysis is mainly multi-Logistic regression analysis.Results: Finally, we brought72colorectal adenocarcinoma into case group, and128healthy people into control group. Between these two groups, the difference of age andgender were not significant.Multi-factor analysis of CYP2R1(+) case group and control showed, serum25(OH)vitamin D3is a protective factor of CYP2R1(+) colorectal cancer (P_trend<0.001), theOR(95%CI) was0.07(0.02,0.24)(the highest vitamin D level compare to the lowestvitamin D level).Multi-factor analysis of CYP2R1(-) case group and control showed, serum25(OH)vitamin D3is a protective factor of CYP2R1(-) colorectal cancer (P=0.030), the OR(95%CI) was0.26(0.08,0.88)Multi-factor analysis of CYP2R1(+) case group and CYP2R1(-) case group showed, the difference of serum25(OH)vitamin D3level between CYP2R1(+) case group andCYP2R1(-) case group was not significant (P=0.531).Conclusion: The results did not find interaction between vitamin D and CYP2R1. VitaminD was a protective factor of colorectal cancer, and the protective function was independentof CYP2R1.