"Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has."

Margaret Mead

Review article
peer-reviewed

Vitamin D and Gastric Cancer: A Ray of Sunshine?



Abstract

Gastric cancer (GC) is one of the most aggressive malignancies, currently ranking third among cancers leading to death worldwide. Despite the recent advancements in GC research, it is most often diagnosed during the terminal stages and with limited treatment modalities contributing to its poor prognosis and a lower survival rate.

Much research has provided conflicting results between a vitamin D deficient status and the development of GC. Vitamin D is a well-known and essential hormone classically known to regulate calcium and phosphate absorption, enabling adequate mineralization of the skeletal system. However, the function of vitamin D is multidimensional. It possesses unique roles, including acting as antioxidants or immunomodulators while crossing the cell membrane, performing several intracellular functions, participating in gene regulation, and controlling the proliferation and invasion of cancer cells, including those of GC.

In light of this, it is imperative to analyze the causes of GC, review the factors that can be used to enhance the effectiveness of treatments, and discover the tools to determine prognosis, reduce mortality, and prevent GC development. In this review, we have summarized recent investigations on multiple associations between vitamin D and GC, emphasizing genetic associations, vitamin D receptors, and the prevalence of hormone deficiency in those developing this aggressive malignancy.

Introduction & Background

Gastric cancer (GC) is one of the five most common cancers to occur globally despite its abatement in incidence during recent years [1,2]. This aggressive malignancy manifests a poor prognosis due to its advanced stage of diagnosis and restricted treatment alternatives, placing GC third among cancers leading to mortality worldwide [3,4]. Furthermore, numerous risk factors such as genetics, Helicobacter pylori (most common), smoked foods, red meat, smoking, and alcohol also contribute to the development of GC [5-8]. Additionally, many investigations also support the significance of vitamin D in the overall pathogenesis of GC at both genetic and molecular levels.

Despite its essential properties as a fat-soluble vitamin, vitamin D is also an active steroid hormone. Its primary function is bone mineralization by regulating calcium and phosphorus homeostasis. We can obtain vitamin D from various foods, supplements and via dermal production under the influence of sun exposure. It is available in two forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). However, since both forms are inactive, they must be hydroxylated twice before activating the final product. The initial activation happens in the liver, followed by the second in the kidneys by enzymes 25-hydroxylase and 1alpha-hydroxylase (1α-hydroxylase) respectively to produce 1,25-dihydroxyvitamin D3 (1,25(OH)2Vitamin D3) (active form), which exerts the physiological effect [6,9,10]. Figure 1 shows the formation and activation of vitamin D3.

Moreover, many studies have highlighted the active participation of vitamin D in other processes like the immune system, inflammation, gene regulation, signal transduction, and finally, the development of cancer. Epidemiological and animal studies mentioned earlier showed that vitamin D exerts an antineoplastic effect via its vitamin D receptor (VDR). Its interaction stimulates apoptosis and differentiation while inhibiting invasion, angiogenesis, proliferation, inflammation, and metastasis [11,12]. In addition, the VDR functions as a transcription factor, regulating several gene expressions.

Since vitamin D is essential in the control and maintainance of many of the crucial tasks within the human body, its deficiency can contribute to immune dysregulation. In infections like Helicobacter pylori, vitamin D deficiency can lead to the failure of its removal [13,14]. Similarly, GC patients may demonstrate a greater survival rate with adequate vitamin D levels as compared to individuals with VDD [10], suggesting that vitamin D could be a powerful constituent in the GC mechanism. This review focuses on various associations between vitamin D and the pathogenesis of GC, which may be beneficial for early diagnosis and treatment. Overall, it provides an understanding of delaying the progression of GC and lowering its associated mortality rate.

Review

Methods

The literature was searched in the PubMed database. The regular keywords used in the search for vitamin D are as follows: Vitamin D, Cholecalciferol, Calcitriol, Drisdol, 1,25dihydroxycholecalciferol, Ergocalciferol, VitaminD2, VitaminD3; For GC, we used keywords such as Stomach cancer, Stomach neoplasm, Stomach tumor, Stomach carcinoma, Gastric carcinoma, Gastric cancer, Gastric tumor, Gastric neoplasm. The Boolean search strategy was applied using "OR" in the regular keywords, giving 92,292 and 161,726 results for vitamin D and GC, respectively. Regular keywords were then combined using the Boolean term "AND" that generated 1,48,274 papers. We also used Medical Subject Headings (MeSH) keywords such as “Vitamin D” and “Stomach Neoplasms” that produced 61,722 and 99,898 articles, respectively. The Boolean term “AND” was implemented on MeSH keywords, which gave us 48 papers. Finally, both regular and MeSH keywords together yielded 119 articles.

Results

Only studies in the English language were included, which reduced the number of articles from 119 to 113. These 113 papers were screened based on the relevant topic, and any articles with animal studies were excluded. Fifty articles were retrieved that were either free full text or abstracts. Table 1 and Table 2 present a summary of the most relevant study characteristics.

Author Country Year  Study design                                          Key findings
Pan et al. [15] China 2010 Experimental VD, in combination with trichostatin A/sodium butyrate and 5-aza-2’deoxycytidine, promotes apoptosis in gastric cancer cells via raising PTEN expression.
Baek et al. [16] Korea 2011 Experimental VD reduces gastric cancer cell survival by suppressing Hh signaling and is synergistic with anti-cancer drugs (Adriamycin, Vinblastine, and Paclitaxel).
Cong et al. [17] China 2015 Case-Control VDR FokI polymorphism and GC risk have a positive relationship.
Chang et al. [18] China 2015 Experimental VD restricts gastric cancer cell proliferation by stimulating miR-145 expression.
Zhao et al. [19] China 2019 Experimental VD increases BMP3 expression and delays GC progression.  
Parsamanesh et al. [20] Iran 2019 Case-Control A negative association has been observed between VDR FokI polymorphism and GC risk, whereas VDR TaqI polymorphism has shown a positive relationship with GC.
Durak et al. [21] Turkey 2019 Case-Control GC risk has not been correlated with VDBP, TaqI, and FokI VDR  polymorphisms; VDD deficiency increases GC risk.
Chang et al. [22] China 2019 Experimental VD inhibits GC cell proliferation by upregulating miR-99b-3p expression.
Calcagno et al. [2] Brazil 2019 Review VD produces an anti-cancer effect in gastric cancer by regulating histone acetylation.
Qadir et al. [23] India 2021 Case-Control The BsmI VDR polymorphism has been linked to GC risk; ApaI and TaqI VDR polymorphisms have not been attributed to GC risk.
Hoseinkhani et al. [24] Iran 2021 Case-Control FokI VDR polymorphism is associated with GC risk; However, TaqI, ApaI, and BsmI VDR polymorphisms are not related to GC risk.
Author Country Year Study design                                         Key findings
Ren et al. [10] China 2012 Retrospective-Observational VDD has been linked to a poor prognosis of gastric cancer.
Bao et al. [7] China 2014 Experimental VD and Cisplatin promote apoptosis and cell cycle arrest in gastric cancer cells in a synergistic fashion.
Wen et al. [25] China 2015 Experimental VDR expression is lowest in gastric cancer compared to precancerous and normal gastric tissue.
Khayatzadeh et al. [26] Iran 2015 Meta-analysis GC has no relationship with VD level or consumption.
Vyas et al. [8] USA 2016 Case-Control VDD is correlated with a higher risk of gastric adenocarcinoma.
Du et al. [27] China 2017 Review The risk and mortality from gastric cancer are higher in VDD.
Yildirim et al. [14] Turkey 2017 Prospective-Observational VDD is correlated with the failure of Helicobacter pylori elimination.
Parizadeh et al. [28] Iran 2019 Review Ultraviolet B radiation reduces the risk of gastric cancer; VDD increases the risk of mortality in GC.
Kwak et al. [29] Korea 2020 Cross-Sectional VDD is considered a risk factor for GC.
Hedayatizadeh-Omran et al. [30] Iran 2020 Case-Control An increased prevalence of VDD has been found in GC; VDD is more prominent in high-grade GC.

Genetic role of vitamin D in gastric cancer

Genetic Polymorphism 

Vitamin D is a vital hormone synthesized for the adequate functioning of normal and healthy tissues. It performs its function by binding to VDR plus one of the retinoid X receptors (RXR) to produce a complex. The complex translocates inside the cell nucleus and binds to vitamin D response elements (VDRE) to further regulate the transcription of its target genes [31]. The gene encoding VDR is located on chromosome 12q13.1 [32,33]. Several VDR gene polymorphisms are linked to cancers, including colon, breast, ovarian, prostate cancer, and melanoma [34]. The most common VDR gene polymorphisms along with their location are: FokI (rs2228570) in exon2 in the 5’ end of the VDR gene [35], and TaqI (rs731236) in exon9, BsmI (rs544410), and ApaI (rs7975232) in intron 8 of the 3’ end region of the VDR gene [36,37]. Numerous studies have mentioned the association of these polymorphisms with the development and progression of GC.

Cong et al. demonstrated the relationship between the FokI polymorphism of the VDR gene to the risk of developing GC. In the FokI polymorphism, the nucleotide ATG becomes substituted with ACG in the first start codon, where translation begins. The latter results in the allele change from “f” to “F.” The f allele, when compared to F, bears an association with an increased risk of GC, a higher level of c-reactive protein (CRP), and more inadequate GC differentiation, contributing to the poor prognosis produced by GC [17]. Similarly, another study describes a positive correlation between the FokI polymorphism with GC susceptibility (p= 0.021). In contrast, other VDR polymorphisms (BsmI, ApaI, and TaqI) have no significant associations with the risk of GC compared to the healthy groups [24].

However, Parsamanesh et al. found that rather than FokI, the TC genotype of TaqI VDR polymorphism is related to the risk of GC (p = 0.002, OR: 2.39) [20]. Likewise, Durak et al. observed that FokI and TaqI polymorphisms of the VDR did not correlate with the susceptibility of GC (p > 0.05), yet found a higher number of the t allele of the TaqI variant in the advanced stage GC, suggesting a nexus between the t allele and a poorer prognosis for GC. In their research, authors assert that VDD strongly correlates with increased GC susceptibility, but the gene polymorphism of vitamin D binding protein (VDBP; rs7041) does not [21]. In addition, another investigation discovered that the BsmI polymorphism is strongly related to GC development, particularly in patients with a high BMI, yet ApaI and TaqI are not. Additionally, ApaI, TaqI, and BsmI variants of the VDR gene markedly limit GC survival [23].

Epigenetics

Calcagno et al. describe the effect of vitamin D on epigenetics. Epigenetics refers to a heritable trait that induces alteration in gene expression without changing the DNA sequence [38]. One of the unique epigenetic mechanisms is histone post-translational alterations. Histone acetylation and DNA methylation have a significant impact on cancer prognosis and treatment results. Histone acetylation results from a dynamic equilibrium between histone acetyltransferases (HATs) and deacetylases (HDACs). Histone acetylation causes gene activation, whereas its deacetylation leads to the silencing of genes. HDAC expression is high in GC, causing a lower expression of tumor suppressor genes (TSGs). Interestingly, vitamin D activates HATs and boosts the expression of TSGs, serving as an anti-cancer agent by modifying epigenetic pathways, which VDRs usually regulate in GC [2].

Pan et al. established the relation between vitamin D and the TSG phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Vitamin D enhances GC cell death by triggering PTEN upregulation through VDR-mediated suppression of the PTEN promoter methylation. VDR synergistically stimulated PTEN overexpression with transcription factors like early growth response gene-1 (Egr-1) and HAT (P300). Additionally, vitamin D amplifies PTEN expression and accelerates apoptosis in GC cells, particularly when accompanied by epigenetic modifiers like HDAC inhibitors (trichostatin A/TSA and sodium butyrate) and DNA methylation inhibitors (5-aza-2’deoxycytidine/5aza). These data suggest that vitamin D coupled with epigenetic modifiers could benefit patients with GC as a promising treatment modality [15].

According to Zhao et al., cancer pathogenesis involves the blockage of several TSGs due to their promoter's methylation. Bone morphogenetic protein 3 (BMP3) is a known TSG, downregulated and expressed in low quantities in GC, owing to promoter hypermethylation. Moreover, VDRE is present in the methylation region of the BMP3 gene promoter. Vitamin D, along with its receptor, is found to bind to these VDREs (p= <0.05), inhibiting BMP3 promoter methylation and increasing the expression of the TSGs in gastric cancer cells. The apparent strength in association suggests the relation between vitamin D and the BMP3 gene, plus the anti-cancer effect of vitamin D in GC via suppression of BMP3 methylation [19].

Vitamin D regulation and cancer progression

Vitamin D has been related to cancer through many signaling mechanisms [39]. The hedgehog (Hh) signaling system has been associated with the advancement of many cancers, including GC [40]. An experimental investigation uncovered a relationship between vitamin D and the Hh signaling system, promoting the survival of GC cells. GC cells treated with vitamin D lowered Hh signaling target genes, signifying that the vitamin can weaken the GC cell survival. Furthermore, vitamin D acts synergistically with anti-cancer drugs such as Adriamycin®, paclitaxel, and vinblastine, thereby increasing the survival of GC patients [16].

Vitamin D regulates several genes, including micro RNAs (miRNA), which play a significant role in cancer development [41-43] and anti-tumor activities [44,45]. miRNAs are chief regulators of messenger RNA (mRNA) and can potentially modify the cell cycle, cell proliferation, cell invasion, and apoptosis. Alteration of specific miRNA can lead to cancer development, partially due to their behavior as oncogenes or TSGs in cancer cells. GC shows lower miRNA-145 (miR-145) than normal gastric tissue [46]. Chang et al. describe vitamin D's effect on miR-145 expression in GC cells. The authors observed that vitamin D promoted miR-145 expression, resulting in expanding cells in the S-phase and decreasing cells in the G2/M-phase of the cell cycle, explaining that miR-145 prevented the S to G2 transition in GC cells in vitro. Vitamin D also inhibits E2F transcription factor 3 (E2F3) found to be upregulated in GC, cyclin-dependent kinase 6 (CDK6), prime targets of miR-145, and the subsequent E2F3 regulated cell cycle genes such as cyclin-dependent kinase2 (CDK2) and cyclinA2 (CCNA2). As a result, vitamin D can exert its anti-cancer activity via overexpression of miR-145 [18].

Chang et al. have additionally revealed another vitamin D-regulated miRNA (miR-99b-3p). They discovered that like miR-145, miR-99b-3p was reduced in GC cells and that VDR increased miR-99b-3p expression in GC cells. Unlike miR-145, vitamin D and miR-99b-3p inhibit homeobox D3 (HOXD3) protein, primarily expressed in GC cells. In contrast to miR-145, miR-99b-3p increases cells in the G1 phase and reduces them in the S phase, implying that miRNA-99b-3p prevents the G1-S transition in the GC cell cycle [22]. VDR-mediated miRNA regulation appears to be one of the critical mechanisms in vitamin D's antiproliferative activity based on the studies mentioned above. Figure 2 illustrates the anti-tumor action of vitamin D.

Vitamin D deficiency and GC association

Several solid tumors (particularly the stomach, colon, liver and gallbladder, pancreatic, lung, female breast, prostate, bladder, and kidney cancers) appear to be reduced by adequate vitamin D levels [47]. Ren et al. measured vitamin D in GC and discovered that 8.1% of patients had sufficient levels (>75nmol/L), 34% had inadequate levels (50-75 nmol/L), and 57.9% had deficient levels (50nmol/L). Vitamin D level was also inversely related to tumor staging and lymph node metastasis, while tumor size, position, differentiation, and distant metastasis had no significant relationship. Furthermore, the five-year survival rate was 57.8% in the group with high vitamin D levels and 43% in the group with low vitamin D levels; vitamin D levels were indicated to be an independent prognostic factor and were comparable to bad prognosis in GC [10].

As VDR mediates vitamin D activity, Wen et al. evaluated the expression of VDR in normal, precancerous, and cancerous gastric tissues. They compared it with the clinicopathological characteristics of GC patients; They found VDR expression was markedly reduced in GC tissues versus healthy and precancerous tissues; secondly, well and moderately differentiated tissues demonstrated profound VDR expression in contrast with the poorly differentiated ones. Finally, VDR was expressed in large quantities in smaller gastric tumors than larger ones [25].

Vyas et al. concluded that the prevalence of VDD in patients with gastric adenocarcinoma was significantly higher when compared to patients with normal vitamin D levels (83.7 % vs. 63.27 %), suggesting a significant relationship between VDD and gastric adenocarcinoma. However, they declared no association between the degree of deficiency and the staging of GC like the above study [8].

To further understand the impact of vitamin D in GC, various studies with distinctive designs have been performed. The majority of ecological investigations using ultraviolet B exposure (UVB) reduced the incidence and mortality of GC [27,28]. A recent study by Kwak et al. discovered that patients with low vitamin D levels have a higher predilection for developing GC. They observed that the odds ratio (OR) for GC was 0.52 (95% CI: 0.30, 0.92) in the arm with increased total vitamin D levels (≤ 20ng/mL), compared to the decreased total vitamin D levels (<12ng/mL) with a p-value of 0.030; This signifies that higher vitamin D levels have a lower prevalence of GC and vice versa [29].

Hedayatizadeh et al. noticed a higher prevalence of VDD in GC cases than controls, with an evident decline in vitamin D concentration in high-grade GC cases. However, no correlations were found between lymph node metastasis, distant metastasis, tumor site, and vitamin D concentration [30]. On the contrary, in a meta-analysis conducted by Khayatzadeh et al., no significant relationship between vitamin D intake/serum vitamin D status and GC development was elucidated [26]. Consistent with this, a few more further studies revealed no correlation between vitamin D level and risk of GC [9,48].

The function of vitamin D in the immune system is widely understood. Numerous investigations have established the relation between VDD and infectious diseases [49, 50]. Yildirim et al. disclosed the relationship between the failure of eliminating HP in vitamin D deficient patients. In their study of 220 patients, elimination was achieved in 170 patients (77.2%), and 50 patients (22.7%) had a failure, with mean vitamin D levels substantially lower in the elimination failure group than in the successful treatment group (9.13 ± 4.7 vs. 19.03 ± 8.13; p= 0.001) [14]. A recent study that supports this notion was published by Yang et al., including results that patients with VDD had a slower elimination rate of HP (OR=0.09; 95%CI=0.2,0.4). Moreover, they reported that the average vitamin D level was higher in HP-negative individuals than the HP-positive individuals [13]. Based on the above findings, VDD could be a potential cause for the failure to eliminate HP, and adequate levels of vitamin D might be beneficial for the effective elimination of the infection.

On the other hand, Bao et al. reported the synergistic action of vitamin D and anti-cancer drug, cisplatin, against GC. Vitamin D amplified the effect of cisplatin by upregulating the pro-apoptotic protein like BCL2-associated X protein (Bax), enhancing cell cycle regulators such as p21 and p27 [51], and reducing the phosphorylation of phosphatidylinositol 3-kinase/AKT and extracellular-signal-related kinase 1/ERK, kinases implicated in GC cell proliferation and apoptosis [52,53]. Vitamin D potentiates the anti-cancer action of cisplatin by controlling cell proliferation, promoting apoptosis, and arresting GC cells in the G0/G1 phase of the cell cycle [7].

Limitation

Certain limitations exist in our study as the data was gathered only from one database (PubMed); only studies published in English were selected; studies with free full text and pertinent abstracts were solely included, and most of the collected studies were only in vitro studies.

Conclusions

Several studies have been conducted to explore the relationship between vitamin D and GC. We observed a variety of correlations between vitamin D and GC. In most studies, GC patients have shown an increased prevalence of VDD, although few studies on VDD prevalence in GC patients are paradoxical. UVB radiation has been shown in most ecological studies to lessen the incidence and mortality of GC. An adequate vitamin D level has been associated with an increase in the survival rate of GC patients, and a low vitamin D level can be considered as a poor prognostic factor in GC.

Furthermore, variations in the VDR gene have been attributed to an increased risk of various malignancies, including GC. Many VDR gene polymorphisms are associated with the risk of GC. However, various research on VDR gene polymorphisms and GC risk have yielded inconsistent results.

Vitamin D exerts an anti-cancer effect by different mechanisms, such as regulating epigenetic pathways, upregulating the expression of miRNAs, boosting the action of cisplatin, stimulating TSGs, and regulating intracellular signal transduction. We also found that serum vitamin D is lower in the HP-positive patients than negative ones, and vitamin D deficient patients fail to eliminate HP. Based on the facts presented above, we may conclude that vitamin D is a protective factor in GC. It can be utilized as a promising technique to treat GC and increase survival rates by correcting the deficiency of vitamin D. However, additional studies are required to fully assess the genetic association of VDR in GC for a more profound knowledge of how to diagnose and treat the aggressive malignancy early and effectively to maximize the survival outcomes.


References

  1. Fitzmaurice C, Allen C, Barber RM, et al.: Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017, 3:524-48. 10.1001/jamaoncol.2016.5688
  2. Calcagno DQ, Wisnieski F, Mota ER, et al.: Role of histone acetylation in gastric cancer: implications of dietetic compounds and clinical perspectives. Epigenomics. 2019, 11:349-62. 10.2217/epi-2018-0081
  3. Ferlay J, Soerjomataram I, Dikshit R, et al.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015, 136:E359-86. 10.1002/ijc.29210
  4. Guggenheim DE, Shah MA: Gastric cancer epidemiology and risk factors. J Surg Oncol. 2013, 107:230-6. 10.1002/jso.23262
  5. Moradi MT, Yari K, Rahimi Z, Kazemi E, Shahbazi M: Manganese superoxide dismutase (MnSOD Val-9Ala) gene polymorphism and susceptibility to gastric cancer. Asian Pac J Cancer Prev. 2015, 16:485-8. 10.7314/apjcp.2015.16.2.485
  6. Hargrove L, Francis T, Francis H: Vitamin D and GI cancers: shedding some light on dark diseases. Ann Transl Med. 2014, 2:9. 10.3978/j.issn.2305-5839.2013.03.04
  7. Bao A, Li Y, Tong Y, Zheng H, Wu W, Wei C: 1,25-Dihydroxyvitamin D₃ and cisplatin synergistically induce apoptosis and cell cycle arrest in gastric cancer cells. Int J Mol Med. 2014, 33:1177-84. 10.3892/ijmm.2014.1664
  8. Vyas N, Companioni RC, Tiba M, et al.: Association between serum vitamin D levels and gastric cancer: a retrospective chart analysis. World J Gastrointest Oncol. 2016, 8:688-94. 10.4251/wjgo.v8.i9.688
  9. Chen W, Dawsey SM, Qiao YL, et al.: Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers. Br J Cancer. 2007, 97:123-8. 10.1038/sj.bjc.6603834
  10. Ren C, Qiu MZ, Wang DS, et al.: Prognostic effects of 25-hydroxyvitamin D levels in gastric cancer. J Transl Med. 2012, 10:16. 10.1186/1479-5876-10-16
  11. Ben-Shoshan M, Amir S, Dang DT, Dang LH, Weisman Y, Mabjeesh NJ: 1alpha,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther. 2007, 6:1433-9. 10.1158/1535-7163.MCT-06-0677
  12. Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ: The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014, 14:342-57. 10.1038/nrc3691
  13. Yang L, He X, Li L, Lu C: Effect of vitamin D on Helicobacter pylori infection and eradication: a meta-analysis. Helicobacter. 2019, 24:e12655. 10.1111/hel.12655
  14. Yildirim O, Yildirim T, Seckin Y, Osanmaz P, Bilgic Y, Mete R: The influence of vitamin D deficiency on eradication rates of Helicobacter pylori. Adv Clin Exp Med. 2017, 26:1377-81. 10.17219/acem/65430
  15. Pan L, Matloob AF, Du J, et al.: Vitamin D stimulates apoptosis in gastric cancer cells in synergy with trichostatin A /sodium butyrate-induced and 5-aza-2'-deoxycytidine-induced PTEN upregulation. FEBS J. 2010, 277:989-99. 10.1111/j.1742-4658.2009.07542.x
  16. Baek S, Lee YS, Shim HE, Yoon S, Baek SY, Kim BS, Oh SO: Vitamin D3 regulates cell viability in gastric cancer and cholangiocarcinoma. Anat Cell Biol. 2011, 44:204-9. 10.5115/acb.2011.44.3.204
  17. Cong L, Wang WB, Liu Q, Du JJ: FokI polymorphism of the vitamin D receptor gene is associated with susceptibility to gastric cancer: a case-control study. Tohoku J Exp Med. 2015, 236:219-24. 10.1620/tjem.236.219
  18. Chang S, Gao L, Yang Y, et al.: miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 by directly targeting E2F3 in gastric cancer cells. Oncotarget. 2015, 6:7675-85. 10.18632/oncotarget.3048
  19. Zhao Y, Cai LL, Wang HL, et al.: 1,25-Dihydroxyvitamin D3 affects gastric cancer progression by repressing BMP3 promoter methylation. Onco Targets Ther. 2019, 12:2343-53. 10.2147/OTT.S195642
  20. Parsamanesh N, Moossavi M, Tavakkoli T, Javdani H, Fakharian T, Moossavi SZ, Naseri M: Positive correlation between vitamin D receptor gene TaqI variant and gastric cancer predisposition in a sample of Iranian population. J Cell Physiol. 2019, 234:15044-7. 10.1002/jcp.28145
  21. Durak Ş, Gheybi A, Demirkol Ş, et al.: The effects of serum levels, and alterations in the genes of binding protein and receptor of vitamin D on gastric cancer. Mol Biol Rep. 2019, 46:6413-20. 10.1007/s11033-019-05088-9
  22. Chang S, Gao Z, Yang Y, et al.: miR-99b-3p is induced by vitamin D3 and contributes to its antiproliferative effects in gastric cancer cells by targeting HoxD3. Biol Chem. 2019, 400:1079-86. 10.1515/hsz-2019-0102
  23. Qadir J, Majid S, Khan MS, Wani MD: Association of Vitamin D receptor gene variations with gastric cancer risk in Kashmiri population. Mol Biol Rep. 2021, 48:3313-25. 10.1007/s11033-021-06376-z
  24. Hoseinkhani Z, Rastegari-Pouyani M, Tajemiri F, Yari K, Mansouri K: Association of vitamin D receptor polymorphisms (FokI (Rs2228570), ApaI (Rs7975232), BsmI (Rs1544410), and TaqI (Rs731236)) with gastric cancer in a Kurdish population from west of Iran. Rep Biochem Mol Biol. 2021, 9:435-41. 10.52547/rbmb.9.4.435
  25. Wen Y, Da M, Zhang Y, Peng L, Yao J, Duan Y: Alterations in vitamin D signaling pathway in gastric cancer progression: a study of vitamin D receptor expression in human normal, premalignant, and malignant gastric tissue. Int J Clin Exp Pathol. 2015, 8:13176-84.
  26. Khayatzadeh S, Feizi A, Saneei P, Esmaillzadeh A: Vitamin D intake, serum Vitamin D levels, and risk of gastric cancer: a systematic review and meta-analysis. J Res Med Sci. 2015, 20:790-6.
  27. Du C, Yang S, Zhao X, Dong H: Pathogenic roles of alterations in vitamin D and vitamin D receptor in gastric tumorigenesis. Oncotarget. 2017, 8:29474-86. 10.18632/oncotarget.15298
  28. Parizadeh SM, Ghandehari M, Jafarzadeh-Esfehani R, et al.: The relationship between vitamin D status and risk of gastric cancer. Nutr Cancer. 2020, 72:15-23.
  29. Kwak JH, Paik JK: Vitamin D status and gastric cancer: a cross-sectional study in Koreans. Nutrients. 2020, 12:2004. 10.3390/nu12072004
  30. Hedayatizadeh-Omran A, Janbabaei G, Alizadeh-Navaei R, Amjadi O, Mahdavi Izadi J, Omrani-Nava V: Association between pre-chemotherapy serum levels of vitamin D and clinicopathologic findings in gastric cancer. Caspian J Intern Med. 2020, 11:290-4. 10.22088/cjim.11.3.290
  31. Haussler MR, Jurutka PW, Mizwicki M, Norman AW: Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)₂vitamin D₃: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab. 2011, 25:543-59. 10.1016/j.beem.2011.05.010
  32. Mittal RD, Manchanda PK, Bhat S, Bid HK: Association of vitamin-D receptor (Fok-I) gene polymorphism with bladder cancer in an Indian population. BJU Int. 2007, 99:933-7. 10.1111/j.1464-410X.2007.06657.x
  33. Zmuda JM, Cauley JA, Ferrell RE: Molecular epidemiology of vitamin D receptor gene variants. Epidemiol Rev. 2000, 22:203-17. 10.1093/oxfordjournals.epirev.a018033
  34. Rai V, Abdo J, Agrawal S, Agrawal DK: Vitamin D receptor polymorphism and cancer: an update. Anticancer Res. 2017, 37:3991-4003. 10.21873/anticanres.11784
  35. Walentowicz-Sadłecka M, Sadłecki P, Walentowicz P, Grabiec M: The role of vitamin D in the carcinogenesis of breast and ovarian cancer [Article in Polish]. Ginekol Pol. 2013, 84:305-8. 10.17772/gp/1581
  36. Abd-Elsalam EA, Ismaeil NA, Abd-Alsalam HS: Vitamin D receptor gene polymorphisms and breast cancer risk among postmenopausal Egyptian women. Tumour Biol. 2015, 36:6425-31. 10.1007/s13277-015-3332-3
  37. Langdahl BL, Gravholt CH, Brixen K, Eriksen EF: Polymorphisms in the vitamin D receptor gene and bone mass, bone turnover and osteoporotic fractures. Eur J Clin Invest. 2000, 30:608-17. 10.1046/j.1365-2362.2000.00686.x
  38. Deans C, Maggert KA: What do you mean, "epigenetic"?. Genetics. 2015, 199:887-96. 10.1534/genetics.114.173492
  39. Deeb KK, Trump DL, Johnson CS: Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer. 2007, 7:684-700. 10.1038/nrc2196
  40. Berman DM, Karhadkar SS, Maitra A, et al.: Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003, 425:846-51. 10.1038/nature01972
  41. Zitman-Gal T, Green J, Pasmanik-Chor M, Golan E, Bernheim J, Benchetrit S: Vitamin D manipulates miR-181c, miR-20b and miR-15a in human umbilical vein endothelial cells exposed to a diabetic-like environment. Cardiovasc Diabetol. 2014, 13:8. 10.1186/1475-2840-13-8
  42. Min D, Lv XB, Wang X, Zhang B, Meng W, Yu F, Hu H: Downregulation of miR-302c and miR-520c by 1,25(OH)2D3 treatment enhances the susceptibility of tumour cells to natural killer cell-mediated cytotoxicity. Br J Cancer. 2013, 109:723-30. 10.1038/bjc.2013.337
  43. Padi SK, Zhang Q, Rustum YM, Morrison C, Guo B: MicroRNA-627 mediates the epigenetic mechanisms of vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice. Gastroenterology. 2013, 145:437-46. 10.1053/j.gastro.2013.04.012
  44. Ting HJ, Messing J, Yasmin-Karim S, Lee YF: Identification of microRNA-98 as a therapeutic target inhibiting prostate cancer growth and a biomarker induced by vitamin D. J Biol Chem. 2013, 288:1-9. 10.1074/jbc.M112.395947
  45. Alvarez-Díaz S, Valle N, Ferrer-Mayorga G, et al.: MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells. Hum Mol Genet. 2012, 21:2157-65. 10.1093/hmg/dds031
  46. Yao Y, Suo AL, Li ZF, et al.: MicroRNA profiling of human gastric cancer. Mol Med Rep. 2009, 2:963-70. 10.3892/mmr_00000199
  47. Grant WB: Lower vitamin-D production from solar ultraviolet-B irradiance may explain some differences in cancer survival rates. J Natl Med Assoc. 2006, 98:357-64.
  48. Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC: Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst. 2006, 98:451-9. 10.1093/jnci/djj101
  49. Sahay T, Ananthakrishnan AN: Vitamin D deficiency is associated with community-acquired clostridium difficile infection: a case-control study. BMC Infect Dis. 2014, 14:661. 10.1186/s12879-014-0661-6
  50. Grant WB: Variations in vitamin D production could possibly explain the seasonality of childhood respiratory infections in Hawaii. Pediatr Infect Dis J. 2008, 27:853. 10.1097/INF.0b013e3181817bc1
  51. Mitrea DM, Yoon MK, Ou L, Kriwacki RW: Disorder-function relationships for the cell cycle regulatory proteins p21 and p27. Biol Chem. 2012, 393:259-74. 10.1515/hsz-2011-0254
  52. Almhanna K, Strosberg J, Malafa M: Targeting AKT protein kinase in gastric cancer. Anticancer Res. 2011, 31:4387-92.
  53. Yao J, Qian CJ, Ye B, Zhang X, Liang Y: ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism. Life Sci. 2012, 91:186-93. 10.1016/j.lfs.2012.06.034

Review article
peer-reviewed

Vitamin D and Gastric Cancer: A Ray of Sunshine?


Author Information

Suchitra Shah Corresponding Author

Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

Zafar Iqbal

Emergency Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

Mohammed G. Alharbi

Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

Harjeevan S. Kalra

Internal Medicine/Emergency Medicine/Oncology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

Megha Suri

Pediatrics/Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

Nitin Soni

Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

Nkiruka Okpaleke

Psychiatry and Behavioral Sciences, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

Shikha Yadav

Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

Pousette Hamid

Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA


Ethics Statement and Conflict of Interest Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.



Review article
peer-reviewed

Vitamin D and Gastric Cancer: A Ray of Sunshine?


Figures etc.

SIQ
7.0
RATED BY 2 READERS
CONTRIBUTE RATING

Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. Learn more here.