Progress in research on vitamin D and tumor related diseases

Department of Endocrinology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China

【Key words】 Vitamin D tumor

The research on vitamin D for decades has focused on the regulation of calcium and phosphorus metabolism. In recent years, vitamin D has been confirmed to have a wider range of biological effects, including inhibiting the proliferation of various types of cells, inducing apoptosis and differentiation, and regulating The function of the body's immune system. Michael et al [1] found that most tissues and cells in the body have vitamin D receptors and converts circulating 1,25(OH)D into active 1,25(OH)2D3 invertase. It provides some new insights into the function of this vitamin, which plays an important role in reducing the incidence of some chronic diseases, including common tumors, autoimmune diseases, infectious diseases, and heart diseases. Related studies have shown that 1,25(OH)2D3 can inhibit tumor cell proliferation and promote tumor cell differentiation. Many studies have found that 1,25(OH)2D3 and its analogues are used for prostate cancer, breast cancer, skin cancer and lung cancer. It has the effect of inhibiting proliferation and promoting apoptosis, and has synergistic effect with other anti-tumor drugs to prevent tumor growth and metastasis.
1 Vitamin D source, metabolism Vitamin D is both a vitamin and a steroid hormone, divided into endogenous and exogenous, endogenous is 7 ~ dehydrocholesterol in human skin through the wavelength of 290 ~ 320 The ultraviolet radiation of mm is first converted into a vitamin D3 precursor, which is gradually converted into vitamin D3 (cholecalciferol) under the action of body temperature. Vitamin D is absorbed in the small intestine as chylomicrons, which promote its absorption. In the blood combined with alpha globulin (DBP) transport, first in the liver mitochondria through the 25-hydroxylase system into 25  (OH) D, and then transported to the renal proximal convoluted tubule epithelial cells in the mitochondria through 1 hydroxy The enzyme acts to produce 1,25(OH)2D3, which is the most active derivative of vitamin D metabolism. In recent studies, vitamin D has been found to have important effects on the intestines, bones, and kidneys, as well as vitamin D receptors in skin keratinocytes, islet cells, lymphocytes, and promyelocytes. In addition, 1,25 (OH 2D3 also has a profound effect on the proliferation and differentiation of lymphocytes, monocyte macrophages and thymocytes. As an immunoregulatory factor, 1,25(OH)2D3 has also attracted people's attention.
2 Vitamin D receptor structure and function Vitamin D receptor (VDR) belongs to the steroid hormone/thyroid hormone receptor superfamily, which exists in the target cell nucleus and is a biological effect of 1,25(OH)2D3. Nuclear receptors can be divided into multiple functional regions, of which A/B is a weak autonomic regulatory domain, D is a hinge, which may be related to localization, while C and E are the main VDRs. The functional region, the C region is the DNA binding region (DBD), which is mainly involved in DNA sequence recognition, and is also partially involved in the formation of heterodimers [2]: the E region is the ligand binding functional region (LBD), and its main function is to bind the ligand. , forming a heterodimeric VDR/RXR with the retinoic acid X receptor (RXR), a ligand-dependent transcriptional activation region at the carboxy terminus of this region, called AF-2, which can synergize with the AF region of the C region [ 2]. Therefore, VDR is essentially a ligand-dependent nuclear transcription factor, which plays an important role in maintaining calcium and phosphorus metabolism and regulating cell proliferation and differentiation. The expression of VDR is related to the degree of differentiation of human cancer cell lines, and it can be used as one of the biological indicators for predicting the prognosis of cancer patients. 1, 25(OH)2D3 has direct and indirect regulation on tumor cells, and the direct effect is that 1,25(OH)2D3 specifically binds to VDR in the nucleus of tumor cells, and then combines VDR with retinoid receptor to form a complex. The complex is capable of binding to a functional element of a promoter region of a corresponding gene of interest, initiating or inhibiting transcriptional activity of the gene; indirectly acting to regulate the transcription of genes of other cells, such as modulating CD8+ CTL cells to produce an anti-tumor cytokine Thus, indirectly affecting the growth and differentiation of tumor cells.
3 1,25(OH)2D3 and tumor in vitro studies show that [3],1,25(OH)2D3 can promote the differentiation of peripheral monocytes into phagocytic cells and promote the differentiation of monocytes and macrophages into osteoclasts. It accelerates bone resorption and inhibits lymphocytes, but has no significant effect on phagocytic function and bactericidal ability of granulocytes. It has a regulating effect on the growth and differentiation of leukemia cells, tumor cells and skin cells. Studies on the anti-tumor mechanism of 25(OH)2D3 have shown that in addition to the above mechanisms, it also includes induction of cell cycle arrest and apoptosis, as well as inhibition of tumor cell growth and inhibition of telomerase activity by reducing the activity of IGF. Inhibition of tumor metastasis, invasion and angiogenesis. The cell cycle dynamics of tumor cells is characterized by abnormality of G1 phase→S phase control point of tumor cells, and the cell population is distributed in the S phase of active DNA synthesis, while the differentiated cell population is mainly distributed in G1/G0 phase of DNA synthesis. Therefore, the G1 phase is considered to be the cell differentiation phase, and the cell arrest in the G1 phase can be used as a predictor of differentiation. The new study found that 1,25(OH)2D3 inhibits the growth of tumor cells by inhibiting the progression of the tumor cell cycle [4], which can induce multiple types of cells to stay in the G1 phase of the cell cycle, while S phase cells The number is reduced, that is, the G1 phase is blocked. 1,25(OH)2D3 has a growth inhibitory effect on malignant cells such as breast cancer cells, skin cancer cells, bladder cancer, prostate cancer, osteosarcoma cells, lung cancer and colon cancer, and can induce human granulocyte leukemia cells to monocytes. Differentiation [5].
3.1 1,25(OH)2D3 and breast cancer Breast cancer is a malignant tumor that seriously threatens women's health. A large number of studies have been conducted on its etiology at home and abroad. Berger discovered in 1988 that VDR is present in normal breast and other epithelial tissues. In 2000, Colston et al [6] found that the concentration of 1,25(OH)2D3 in the circulation increased during pregnancy and lactation. It has been proved that there is 1α-hydroxylase in normal breast tissue. 1,25(OH)2D3 plays an important role in the formation and differentiation of milk. 1,25(OH)2D3 binds to vitamin D receptor and inhibits the growth and metastasis of breast cancer cells [7]. Bcl 2 gene is a recognized anti-apoptotic gene, bcl 2 is common in estrogen receptor-positive breast cancer, Wang et al [8] found that estrogen can significantly increase the level of bcl 2 mRNA, and can protect MCF  7 Cells are protected from apoptosis. Breast cancer is a systemic disease, and its therapeutic effect is not limited to the size of surgery. The proportion of comprehensive treatment in survival rate is more and more important. With the development of non-classical effects of vitamin D, the researchers found that 1,25(OH)2D3 has a role in promoting apoptosis of breast cancer cell lines, and it is more effective in combination with chemotherapy drugs and radiation therapy. Tamoxifen (TAM) has been widely used in the treatment of estrogen receptor-positive breast cancer. However, TAM tolerance and tumor progression during drug administration are clinical problems that cannot be ignored. Liu Jing et al [9] showed that 1,25 (OH) 2D3 and TAM can down-regulate the expression of bcl  2, the two drugs combined with bcl  2 almost no expression, combined with the combination of the two MCF  7 cells increased apoptosis, It shows that the combination of the two can effectively eliminate tumor cells and protect normal human cells, which has a synergistic effect. The selective estrogen receptor modulator (SERM) represented by Tamoxifen (TAM) is currently the most representative endocrine therapy for the treatment of breast cancer, because it can only partially estrogen receptors. Positive breast cancer patients benefit, and estrogen receptor-negative patients are highly susceptible to drug resistance [10], which limits their efficacy. Lang Haibin et al [11] found that 1,25 (OH) 2D3 target-controlled estrogen receptor alpha expression vector combined with tamoxifen can prevent the cycle progression of estrogen receptor alpha negative MDA  MB 231 breast cancer cells and It induces apoptosis, which restores the chemosensitivity of breast cancer cells that were originally tolerant to tamoxifen. Radiotherapy is an important treatment, especially in breast-conserving treatments. Li Bingyan et al [12] found that after combination of 1,25(OH)2D3 and radiation, MCF-7 cells were arrested in both G1 and G2, and S phase was delayed, so 1,25(OH)2D3 could increase γ-rays. The ability to kill breast cancer cells. In the treatment of breast cancer, 1,25(OH)2D3 is expected to become a new generation of adjuvant drugs.
3.2 1,25(OH)2D3 and skin tumors Skin tumors are the most common tumors in humans including malignant melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), the irradiation of purple lines and the occurrence of these tumors, Development is closely related. Ultraviolet rays have a dual effect. On the one hand, excessive ultraviolet radiation can cause DNA damage and cause cancer. On the other hand, ultraviolet light is also beneficial to the human body, because the epidermis uses ultraviolet energy to convert 7-DHC into pre-vitamin D3, which is then converted into activation. Form 1,25(OH)2D3. Liu et al [13] compared 719 patients with SCCHN (human squamous cell carcinoma of the head and neck) with 821 healthy subjects and found that VDR ff and t genotypes can reduce the risk of SCCHN more than normal FF and TT. And regardless of age, gender, ethnicity and other factors, indicating that VDR f and t alleles and their genotypes may be protective genes of SCCHN. Zheng Tianhu et al [14] found that 1,25 (OH) 2D3 can inhibit the proliferation of melanoma cell line A375, and it has a time-dose-dependent, human bcl 2 gene is a recognized anti-apoptotic gene, 1,25 ( OH)2D3 can down-regulate the expression of bcl2, decrease the bcl2 protein, and abolish the effect of bcl2 on inhibiting apoptosis. Paclitaxel can stimulate the phosphorylation of bcl2 protein to inactivate it [15], the same The combination of 25(OH)2D3 can reduce the dosage of paclitaxel and reduce the side effects of drugs. 1,25(OH)2D3 is expected to be a drug for the treatment of melanoma.
3.3 1,25 (OH) 2D3 and prostate cancer Prostate cancer is a serious threat to men's health, and is one of the most common malignant tumors in the male genitourinary system. Studies have shown that vitamin D deficiency is a causative factor in prostate cancer, and high levels of serum 1,25(OH)2D3 can reduce the risk of prostate cancer [16]. Medeiros et al [17] investigated the polymorphism of VDR translation initiation sites in 191 patients undergoing radical prostatectomy. The presence of allele F is directly proportional to the increase in tumor malignancy, ff genotype and tumor The grading was negatively correlated, indicating that the ff genotype has a protective mechanism for prostate cancer development. The study found that the ability of vitamin D to inhibit the proliferation of prostate cancer cells is closely related to the expression of VDR in prostate cancer cells, and is related to the activity of 24-hydroxylase in cancer cells. Vitamin D and anticancer drugs such as paclitaxel are used in prostate cancer cells. It was found that vitamin D can enhance the cytotoxicity of paclitaxel and synergistically inhibit the growth of prostate cancer epithelial cells. Hsu [18] found that 1,25(OH)2D3 has anti-proliferation, differentiation-promoting, anti-metastatic/infiltration effects on prostate epithelial cell carcinoma. Due to the side effects of increased serum calcium, the clinical application of 1,25(OH)2D3 in the treatment of prostate cancer is limited, while the precursor 25  (OH)D of 1,25(OH)2D3 has the characteristic of not increasing blood calcium. And it can be used in the prostate to convert to 1,25(OH)2D3 by the action of 1α-hydroxylase. The activity of 1α-hydroxylase is significantly decreased in prostate cancer cells, and the inhibition of 25(OH)D is mainly dependent on the activity of endogenous 1αhydroxylase, so it is used to prevent and treat prostate cancer. Vitamin D is for further study.
3.4 1,25(OH)2D3 and lung cancer Lung cancer is a malignant tumor that seriously threatens people's life and health. The current treatment mainly includes surgery, chemotherapy and adjuvant treatment of traditional Chinese medicine. Multidrug resistance (MDR) in lung cancer cells against cancer drugs is the main cause of chemotherapy failure, especially the main cause of chemotherapy failure in non-small cell lung cancer (NSCLC). There are several cell cycle regulatory genes in most tumor cells. The changes of cell cycle regulatory genes are closely related to the occurrence and development of tumors. All-trans retinoic acid (ATRA) is an active form of retinoic acid compounds, which has various biological functions such as inhibiting cell growth and promoting cell differentiation. It passes through specific retinoic acid receptors. , RAR) exerts its biological functions. In recent years, it has been found that 1,25(OH)2D3 also has a significant regulatory effect on cell proliferation, differentiation, and immune function, and is mainly expressed in inhibiting the progression of tumor cells [19]. The main mechanism of action of ATRA and 1,25(OH)2D3 against tumors is to regulate the cell cycle, induce apoptosis, etc., all acting on specific DNA sequences on the target gene, so ATRA and 1,25(OH)2D3 are combined. When used, the expression levels of MRP and LRP genes in lung adenocarcinoma can be down-regulated, and chemotherapy sensitivity of lung adenocarcinoma can be improved, resulting in synergistic effect [20]. However, there is no significant effect on the expression levels of MRP and LRP genes in lung squamous cell carcinoma, and there may be other mechanisms to improve the chemosensitivity of lung squamous cell carcinoma. 1,25(OH)2D3 has yet to become a new member of chemotherapy drugs for lung cancer.
3.5 1,25(OH)2D3 and bladder cancer The occurrence and development of bladder cancer is a multi-step process. The long-term accumulation of abnormal genotypes leads to the appearance of malignant phenotype. Hu Shaoqun [21] investigated 37 cases of bladder transitional cell carcinoma. Patients and 40 normal controls. The relationship between TaqI, ApaI, FokI allele polymorphisms of VDR and bladder cancer was studied by polymerase chain reaction (PCR) and restriction enzyme digestion. The alleles of VDR gene TaqI and ApaI restriction sites were found. Gene polymorphisms are not associated with bladder cancer, and allele polymorphisms at the FokI restriction site may be associated with bladder cancer and the ff-type gene may be a high-risk genotype for bladder cancer. The role of 1,25(OH)2D3 in the prevention and treatment of bladder cancer remains to be further studied. In summary, the immunomodulatory function of 1,25(OH)2D3 has been paid more and more attention especially in the prevention and treatment of tumor diseases. The toxic effect of 1,25(OH)2D3 is mainly the occurrence of hypercalcemia, thus limiting the dosage of the application, and thus affecting its anti-tumor effect. With the further study of vitamin D analogues, high doses of vitamin D can be used in small doses and without causing hypercalcemia, making it a promising drug for the prevention and treatment of tumors.

【references】
[1] Michael F, Holick M. Vitamin D deficiency [J]. Endocr Rev, 2007, 619(3): 357266.

[2] Strugnell SA, Deluca HF. The vitamin D receptor-structure and transcriptional activation [J]. Proc Soc Exp Biol Med, 1997, 215(3): 223228.

[3]Zhou Jianyuan. The regulation of new vitamin D derivatives on the growth and differentiation of leukemia cells [J]. Chinese Journal of Hematology, 1990, 11 (9): 458.

[4] Zinser GM, McEleney K, Welsh J. Characterization of mammary tumor cell lines from wild type and vitamin D3 receptor knockout mice [J]. Mol Cell Endocrinol, 2003, 200 (1 2): 67-80.

[5] Vanden-Bemd GJ, Chang GT. Vitamin D and vitamin D analogs in cancer treatment [J]. Curr Drug Targets, 2002, 3 (1): 85-94.

[6] Colston C, Han M. Implicated in the growth regulatory effects of vitamin D in breast cancer [J]. Endocrine Related Cancer, 2001, (9): 45-59.

[7]Barbareschi M, Veronese S, Caffo O, et al. Bcl2 and p53 expression in nodenegative breast carcinoma: a study with long term followup[J].Hum Pathol,1996,27:11491155 .

[8] Wang TTY, Phang JM. Effects of estrogen on apoptotic pathways in human breast cancer cell line MCF  7 [J]. Cancer Res, 1995, 55: 2487  2489.

[9]LIU Jing,ZHAO Haoliang.Effects of 1,25-dihydroxyvitamin D3 and tamoxifen on the growth and apoptosis of breast cancer cells[J].中国药与临床,2007,6(7):7.

[10] Swatn SM. Tamoxifen for patients with estrogen receptor-negative breast cancer [J]. J Clin Oncol, 2001, 19(18 Suppl): 93S-97S.

[11] Lang Haibin, Yan Mantian. Effect of 1,25-dihydroxyvitamin D3 combined with tamoxifen on cell cycle and apoptosis of MDAMB231 transfected with VDRETkERα expression vector[J].第三Journal of Military Medical University, 2006, 5(4): 24-27.

[12] Li Bingyan, Tong Jian, Zhang Zengli. Effects of 1,25-dihydroxyvitamin D3 on radiosensitivity of breast cancer cells[J].Tumor,2007,8(4):1114.

[13] Liu Z, John I. Polymorphisms of vitamin D receptor gene protect against the risk of head and neck cancer [J]. Pharmacogenetics and Genomics, 2005, 15(3): 159165.

[14] Zheng Tianhu, He Yan, Li Yingjie. Effects of vitamin D3 on the growth and apoptosis of melanoma cell lines[J].Journal of Practical Oncology,2006,4(20):81.

[15] Haldars T, Chintapalli J, Croce CM. Taxol induces bcl2 phosphoryldtion and death of prostate cancer cells [J]. Cancer Res, 1996, 56(6): 1221.

[16] Hamasaki T, Inatomi H, Katoh T, et al. Significance of vitamin D receptor genepolymorphism for risk and disease severity of prostate cancer and benign prostatic hyperplasia in Japanese [J]. Urol Int, 2002, 68(4): 226 231.

[17] Medeiros R, Morais A, Vasconcelos A, et al. The role of vitamin D receptor gene polymorphisms in the susceptibility to prostate cancer of a southern European population [J]. Hum Genet, 2002, 4(7): 413-418 .

[18] Hsu TY. The relationship between prostate cells 1α hydroxylase activity decreased and 25(OH)D3 inhibited growth of lower susceptibility[J] . Cancer Res, 2001, 61(7): 28522856.

[19] Zinser GM, McEleney K, Welsh J. Characterization of mammary tumor cell lines from wild type and vitamin D3 receptor knockout mice [J]. Mol Cell Endocrinol, 2003, 200 (1 2): 67-80.

[20] Hu Junfeng, Chen Yuqing, Li Dianmin, et al. Study on apoptosis induced by all-trans retinoic acid in lung cancer cell lines[J]. Journal of Bengbu Medical College, 2005, 30(2): 104107.

[21] Hu Shaoqun. Relationship between vitamin D receptor gene polymorphism and bladder transitional cell carcinoma[J]. China Journal of Modern Medicine, 2006, 16(20): 8994.