Cervical cancer in Folate Points of View

 Kyle J. Norton

 According to the American Cancer Society's, in 2014, 12,360 new cases of invasive cervical cancer will be diagnosed with the death of  4,020 patients. The risk of cervical cancer is higher in Hispanic women followed by African-Americans, Asians and Pacific Islanders, and whites(1).

 Folate, also known as folic acid, vitamin B9, is a water soluble vitamin, found abundantly in leafy vegetables, citrus fruits, beans, whole grain, etc. The vitamin plays an important role in synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions, production of red blood cells for anemia prevention.

Epidemiological studies focusing folate or vitamin B9 in reduced risk of cervical  cancer have produced conflict results(a)(b)(c)(d).
Levels of serum of folate
Suggestion of lower levels of serum of folate or deficiency of folate and vitamin B12  may induce risk of cervical caner. According to a case-control study enrolled 927 Korean women (440 controls, 165 patients with CIN 1, 167 patients with CIN 2/3, and 155 patients with cervical cancer, aged 20-75 years) study by Kyunghee University College of Medicine, serum of folate is associated to reduced risk of cervical cancer but MTHFR variant genotype may increase CIN and cervical cancer risk in women with low folate or vitamin B12 status(2). The Shanxi Medical University, in the study of the effects of folate against human cervical cancer cell line and HPV indicated that different concentration of folate inhibited cervical cancer cell proliferation and enhanced cell apoptosis, but not interaction between folate and HPV16 in cervical cancer cell(3). Also, in regard of serum folate, vitamin B12, MTHFR polymorphisms and serum homocysteine (chemiluminescence assay) among 322 women from Kerala, South India, found that no significant associations between MTHFR polymorphisms, serum homocysteine, and folate levels with cervical carcinogenesis but these parameters acted as effect modifiers of serum vitamin B12, implicating a synergistic role of these 2 vitamins in invasive cervical cancer(4). Other suggestion of high-expression of DNMT1 protein or mRNA and folate deficiency was significantly associated with cervical carcinogenesis(5) and adequate folate could effectively inhibit the proliferation of cervical cancer cells and facilitate their apoptosis in vitro, thus would reverse the aberration protein expression of DNMT1 and MeCP2(6).

The effects
The All India Institute of Medical Sciences,study, alood and tissue samples collected from normal (n = 35), SILs (n = 27), and cervical cancer patients (n = 38) in the age group of 26-70 years, indicated a role of folate and vitamin B(12) in modulating the risk of cervical cancer(7). Women with higher concentrations of serum folate and vitamin B12 may have a beneficial impact on the prevention of CC. and a lower risk of being positive for HR-HPVs, according to the University of Alabama at Birmingham (UAB)(8). Other researchers suggested that  low levels of folate might increase the risk of cervical cancer, and there may be a potential interaction between low level of serum folate and HPV16 in the development of cervical cancer(9) and  Improved folate status in people who are at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer(9). IGFBP3, insulin-like growth factor binding protein 3, decreased associated to the progression of cervical cancer, folic acid increased levels of IGF-BP3, of that lead to inhibition of cervical cancer cell growth(10).


Taking altogether, serum concentration of folate is associated to reduced risk and treatment of cervical cancer and supplement folate may improve people who are at risk of cervical due to HPV infection.
Over doses of folate may induce symptoms of difficulty of coordinating movement, numbness, sensory changes, etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

 
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References
(1) Cerical cancer (Amerrican cancer society)
(a) Diet and premalignant lesions of the cervix: evidence of a protective role for folate, riboflavin, thiamin, and vitamin B12 by Hernandez BY¹, McDuffie K, Wilkens LR, Kamemoto L, Goodman MT.(PubMed)
(b) A case control study of nutritional factors and cervical dysplasia by Liu T¹, Soong SJ, Wilson NP, Craig CB, Cole P, Macaluso M, Butterworth CE Jr.(PubMed)
(c) [Chemoprevention of cervical cancer--intervention study of cervical precancerous lesions by retinamide II and riboflavin].[Article in Chinese] byChen RD.(PubMed)
(d) Epidemiologic studies of vitamins and cancer of the lung, esophagus, and cervix by Ziegler RG.(PubMed)
(2) Common polymorphisms in methylenetetrahydrofolate reductase gene are associated with risks of cervical intraepithelial neoplasia and cervical cancer in women with low serum folate and vitamin B12 by Tong SY¹, Kim MK, Lee JK, Lee JM, Choi SW, Friso S, Song ES, Lee KB, Lee JP.(PubMed)
(3) [Effect of folate on the proliferation of human cervical cancer cell and relationship with HPV16].

[Article in Chinese] by Ding L¹, Ma J, Zhou Q, Wang J.(PubMed)

(4) A case-control nutrigenomic study on the synergistic activity of folate and vitamin B12 in cervical cancer progression by Ragasudha PN¹, Thulaseedharan JV, Wesley R, Jayaprakash PG, Lalitha P, Pillai MR.(PubMed)
(5) Folate deficiency and aberrant expression of DNA methyltransferase 1 were associated with cervical cancerization by Jin-Tao W¹, Ling D, Shi-Wen J, Junxia H, Wei-Min Z, Qin Z, Zuo-Kai Y, Li Z.(PubMed)
(6) [Effect of folate in modulating the expression of DNA methyltransferase 1 and methyl-CpG-bingding protein 2 in cervical cancer cell lines].

[Article in Chinese]by Wang JT¹, Wu TT, Bai L, Ding L, Hao M, Wang Y.(PubMed)

(7) Cervical cancer pathogenesis is associated with one-carbon metabolism by Pathak S¹, Bhatla N, Singh N(PubMed)

(8) Indian women with higher serum concentrations of folate and vitamin B12 are significantly less likely to be infected with carcinogenic or high-risk (HR) types of human papillomaviruses (HPVs) by Piyathilake CJ¹, Badiga S, Paul P, Vijayaraghavan K, Vedantham H, Sudula M, Sowjanya P, Ramakrishna G, Shah KV, Partridge EE, Gravitt PE.(PubMed) 

(9) Folate is associated with the natural history of high-risk human papillomaviruses by Piyathilake CJ¹, Henao OL, Macaluso M, Cornwell PE, Meleth S, Heimburger DC, Partridge EE.(PubMed) 

(10) In vitro downregulation of growth factors by insulin-like growth factor binding protein-3 in cervical cancer. by Mathur RS¹, Mathur SP.(PubMed)