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mRNA expression of human papilloma virus (HPV)16 L1, L2, E6, and E7 in normal, squamous intraepithelial lesion (SIL), and cervical cancer subjects by qRT-PCR. * P < 0.05, * * P < 0.001. (Figure available in color online.)
Source publication
Most cases of cervical cancer are associated with human papilloma virus (HPV) infection of high risk types. In folate deficiency, heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) interferes with HPV16 viral capsid protein synthesis. We aimed to study the importance of 1-carbon metabolism in cervical carcinogenesis by examining serum vitamin B1...
Context in source publication
Context 1
... found a decreased expression of HPV16 L1 mRNA by 6.76 and 14.51 fold in SIL and CC, respectively, when compared to normals (P = 0.09, 0.004 r 2 = -0.560(**) P = 0.002 in mRNA level of HPV16 E7 (P = 0.003, 0.0001) was seen in SIL and CC, respectively, when compared to normals (Fig. 2). No significant difference in hnRNP-E1 mRNA levels was observed (P = 0.17) but a decreasing trend in hnRNP-E1 ex- pression was seen from normal to SIL and CC subjects. No significant correlation was observed between hnRNP-E1 and HPV16L1 and L2 (P = 0.37, 0.13). An inverse and significant correlation was seen between hnRNP-E1 and HPV16 E6 and E7 (P = 0.004, .045). ...
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Citations
... It has been reported that viruses hijacked the host nucleic acid substrates to successfully replicate their genome (Herrmann et al., 2020). FA deficiency perturbs virus maturation after HPV initial infection (Pathak et al., 2014); FA deficiency condition was associated with VSV replication inhibition (Wu et al., 2023). However, intracellular FA is limited and frequently requires exogenous sources to supply under various settings (Lan et al., 2018). ...
... large amount of purine substrate and methylation modifications from the host, which is facilitated by the availability of FA (White et al., 2011;Konan and Sanchez-Felipe, 2014). For instance, SARS-CoV-2 has the capacity to co-opt FA-mediated 1C metabolism with the host to build a novel RNA replication factory ; while FA deficiency has been reported to perturb virus maturation after an initial HPV infection and suppressed viral replication (Pathak et al., 2014). A previous report have shown that the activation of the DNA repair mechanism was associated with Bap exposure (Allmann et al., 2020). ...
Folate receptor alpha (FOLR1) is vital for cells ingesting folate (FA). FA plays an indispensable role in cell proliferation and survival. However, it is not clear whether the axis of FOLR1/FA has a similar function in viral replication. In this study, we used vesicular stomatitis virus (VSV) to investigate the relationship between FOLR1-mediated FA deficiency and viral replication, as well as the underlying mechanisms. We discovered that FOLR1 upregulation led to the deficiency of FA in HeLa cells and mice. Meanwhile, VSV replication was notably suppressed by FOLR1 overexpression, and this antiviral activity was related to FA deficiency. Mechanistically, FA deficiency mainly upregulated apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) expression, which suppressed VSV replication in vitro and in vivo. In addition, methotrexate (MTX), an FA metabolism inhibitor, effectively inhibited VSV replication by enhancing the expression of APOBEC3B in vitro and in vivo. Overall, our present study provided a new perspective for the role of FA metabolism in viral infections and highlights the potential of MTX as a broad-spectrum antiviral agent against RNA viruses.
... Wu et al found that blood B12 levels were substantially lower in menopausal and postmenopausal breast cancer patients, and patients with the lowest B12 levels had an elevated risk of breast cancer [21]. Reduced B12 levels have also been linked to an increased risk of cervical and gastrointestinal tract malignancies [22][23][24]. As a result, B12 supplementation is imperative for vegans due to the extensive and irreversible detrimental effects of the deficiencies. ...
Vegetarianism in any of its various forms, particularly veganism, has been increasing in popularity over the past few years, especially among the young population in the United States. While several studies have shown that a vegan diet (VD) decreases the risk of cardiometabolic diseases, such as cardiovascular disease, type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease, veganism has been associated with adverse health outcomes, namely, nervous, skeletal, and immune system impairments, hematological disorders, as well as mental health problems due to the potential for micro and macronutrient deficits. The goal of this review article is to discuss the current literature on the impact and long-term consequences of veganism on vulnerable populations, including children, adolescents, pregnant and breastfeeding women, and fetal outcomes in strict vegan mothers. It also focuses on the many deficiencies of the vegan diet, especially vitamin B12, and the related increased risk of malignancies.
... In 2012, the worldwide prevalence of cervical cancer women and deaths were 528,000 and 266,000, respectively [3]. Various factors including genetics, immune response, and human papillomavirus (HPV)-16 variants are associated with the increased risk of HPV-induced squamous intraepithelial neoplasia conversion to cancerous lesions [4]. In addition, lipid peroxidation, impaired antioxidant system, and elevated inflammatory biomarkers are involved in the pathogenesis of cervical dysplasia [5,6]. ...
... A previous study has shown that 6-month folate supplementation (5 mg/day) could regress CIN1 and improve homocysteine (Hcy) levels, insulin metabolism, and few markers of inflammation and oxidative stress [9]. In addition, previous studies have reported that folate deficiency and aberrant expression of DNA methyltransferase 1 are associated with an additive effect on cervical cancerization [4,10]. Folate status and aberrant DNA methylation are also correlated with the natural history of HPV infection [11]. ...
Background and Objective
Inconsistent evidence showed that folate supplementation may be associated with reduced risk of cancer due to improved metabolic profiles and reduced markers of oxidative stress and inflammation. The aim of this investigation was to quantify the effects of folate supplementation on the recurrence and other metabolic factors of women with cervical intraepithelial neoplasia grade 2/3 (CIN2/3).
Methods
This randomized, double-blind, placebo-controlled clinical trial was performed among 60 overweight/obese women with CIN2/3. Definitive CIN2/3 confirmation was done via biopsy, pathological diagnosis, as well as colposcopy. Participants were randomly assigned to the intervention group to take 5 mg/day folate supplements or placebo group (n = 30 in each group) for 12 weeks.
Results
The results of the current study showed a non-significant decrease in recurrence of CIN2/3 in the folate group in comparison with the placebo group (3.3% vs. 16.7%, P = 0.08). Compared with the placebo, folate supplementation significantly decreased plasma homocysteine (Hcy) levels (P < 0.001), serum insulin values (in the crude model) (P = 0.01), and homeostasis model assessment of insulin resistance (P = 0.01). Also, folate supplementation resulted in a significant improvement in the quantitative insulin sensitivity check index (P = 0.002) and total antioxidant capacity (P = 0.04) and a significant reduction in high-sensitivity C-reactive protein (P = 0.015) in comparison with the placebo group.
Conclusions
In conclusion, folate supplementation for 12 weeks among overweight/obese women with CIN2/3 showed a non-significant decrease in its recurrence and had beneficial effects on insulin sensitivity, inflammation, and oxidative stress markers.
... [47] This inverse association of serum levels of B 12 and the risk of cancer is also evident in patients with cervical cancer. Pathak et al. (2014) found that cervical cancer patients had significantly lower serum B 12 concentrations when compared to control patients. [48] Furthermore, there was a significantly higher risk of human papillomavirus (HPV) infection when B 12 levels were insufficient. ...
... Pathak et al. (2014) found that cervical cancer patients had significantly lower serum B 12 concentrations when compared to control patients. [48] Furthermore, there was a significantly higher risk of human papillomavirus (HPV) infection when B 12 levels were insufficient. HPV infection has been implicated in the etiology of 70% of cervical cancers. ...
The number of individuals partaking in veganism has increased sharply in the last decade. Therefore, it is critical to look at the implications of vegan diets for public health. Although there are multiple health benefits of a vegan diet, studies have also linked the diet with deficiencies in various micronutrients. This study focuses on vitamin B12, because of its critical role in DNA synthesis and methylation. In light of these connections, we conduct a critical review of recent scientific literature to understand the effects of a B12 deficient diet on the genome and epigenome, and whether it can give rise to cancer. We observe that a B12 deficiency leads to increased uracil misincorporation, leading to impaired DNA synthesis and genomic instability. The deficiency also leads to global hypomethylation of DNA, a hallmark of early carcinogenesis. The findings of this study highlight the need for increased awareness among vegans to ensure adequate B12 intake through supplementation or consumption of fortified products as a preventative measure. Additionally, the biofortification of staple crops and an improved version of fermented products with increased B12 content could be developed when inadequate intake seems otherwise inevitable.
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... Eight studies demonstrated no significant difference in the blood-based levels of IGF-1, IGFBP-3, folate, or IFN-γ in patients with cervical cancer in comparison with controls. [44][45][46][47][52][53][54][55] Supporting Table 4 describes all other studies with potential biomarker candidates identified in this review. These other biomarker candidates were categorized as vitamins, immunologic markers, apoptotic markers, tumor markers, tumor suppressors and oncogenes, sex hormones, growth factors, cell-signaling molecules, matrix metalloproteinases and inhibitors, products of oxidative stress, enzymes, macro-and micromolecules, molecular markers and chromosomal aberrations, or miscellaneous markers. ...
Background
Despite the significant societal burden of human papillomavirus (HPV)–associated cancers, clinical screening interventions for HPV‐associated noncervical cancers are not available. Blood‐based biomarkers may help close this gap in care.
Methods
Five databases were searched, 5687 articles were identified, and 3631 unique candidate titles and abstracts were independently reviewed by 2 authors; 702 articles underwent a full‐text review. Eligibility criteria included the assessment of a blood‐based biomarker within a cohort or case‐control study.
Results
One hundred thirty‐seven studies were included. Among all biomarkers assessed, HPV‐16 E seropositivity and circulating HPV DNA were most significantly correlated with HPV‐associated cancers in comparison with cancer‐free controls. In most scenarios, HPV‐16 E6 seropositivity varied nonsignificantly according to tumor type, specimen collection timing, and anatomic site (crude odds ratio [cOR] for p16+ or HPV+ oropharyngeal cancer [OPC], 133.10; 95% confidence interval [CI], 59.40‐298.21; cOR for HPV‐unspecified OPC, 25.41; 95% CI, 8.71‐74.06; cOR for prediagnostic HPV‐unspecified OPC, 59.00; 95% CI, 15.39‐226.25; cOR for HPV‐unspecified cervical cancer, 12.05; 95% CI, 3.23‐44.97; cOR for HPV‐unspecified anal cancer, 73.60; 95% CI, 19.68‐275.33; cOR for HPV‐unspecified penile cancer, 16.25; 95% CI, 2.83‐93.48). Circulating HPV‐16 DNA was a valid biomarker for cervical cancer (cOR, 15.72; 95% CI, 3.41‐72.57). In 3 cervical cancer case‐control studies, cases exhibited unique microRNA expression profiles in comparison with controls. Other assessed biomarker candidates were not valid.
Conclusions
HPV‐16 E6 antibodies and circulating HPV‐16 DNA are the most robustly analyzed and most promising blood‐based biomarkers for HPV‐associated cancers to date. Comparative validity analyses are warranted. Variations in tumor type–specific, high‐risk HPV DNA prevalence according to anatomic site and world region highlight the need for biomarkers targeting more high‐risk HPV types. Further investigation of blood‐based microRNA expression profiling appears indicated.
... Similarly, low levels of folate also were detected among women with high-grade abnormal cytology or cervical cancer in the USA, Turkey, India, and China [24,26,28,30], and two meta-analyzes corroborate with these results [4,5]. Additionally, studies in China, South Korea, and USA showed a reduced risk of preneoplastic cervical lesions among women with high serum folate levels or dietary folate intake [7,18,25,31e35]. ...
Background & aims
Diet and lifestyle play an important role in etiology of various tumors. Serum concentration of folate and vitamin B12may be associated with carcinogenesis since they are involved in DNA methylation and nucleotide synthesis. However, the role of these micronutrients on development of cervical cancer is still controversial. Thus, the aim of this study was to analyze the association of lower status of folate and vitamin B12 with the risk of pre-neoplastic cervical lesions.
Methods
Our sample group was divided in Control group (n = 120) - women with normal cytology, and Case groups (n = 57) – women presenting Atypical Squamous Cells of Undetermined Significance (ASC-US, n = 21), Low Grade Squamous Intraepithelial Lesion (LSIL; n = 16), and High-Grade lesions (n = 20). We obtained cervical samples for cytology analysis and HPV detection, and blood samples for evaluation of serum concentration of folate and vitamin B12.
Results
No difference of serum folate was observed among Cases and Control groups. On the other hand, women with High-Grade lesions presented significant lower median concentration of vitamin B12 if compared to another groups. Then, we observed increased risk of High-Grade lesions among participants with low vitamin B12 levels was observed in relation to women that presented high levels of the micronutrient and from Control group [OR (95% CI): 2.09 (0.65–6.76), p = 0.216], ASC-US [OR (95% CI): 3.15 (0.82–12.08), p = 0.095], and LSIL [OR (95% CI): 3.10 (0.76–12.70), p = 0.116].
Conclusions
Low concentration of vitamin B12 was associated with an increased risk of High-Grade cervical lesions. Besides, we did not observe any difference of serum folate among women with normal cytology and women with pre-neoplastic cervical lesions.
... Low folate levels may lead to an impairment in these functions, thereby leading to carcinogenesis. [7] It has been further hypothesized that incorporation of the HPV genome into the human genome, which is a critical step in cervical carcinogenesis, occurs at fragile or unstable sites. [8] The instability of the genes in the human DNA may occur due to inadequate DNA precursors including folate. ...
... Low folate levels may lead to an impairment in these functions, thereby leading to carcinogenesis. [7] It has been further hypothesized that incorporation of the HPV genome into the human genome, which is a critical step in cervical carcinogenesis, occurs at fragile or unstable sites. [8] The instability of the genes in the human DNA may occur due to inadequate DNA precursors including folate. ...
... PCBP1 protein is significantly downregulated in multiple primary and metastatic cancers, including gastric cancer (Ji et al., 2017), lung cancer (H. Wang et al., 2010), malignant-transformed moles (Shi et al., 2012), thyroid cancer (M.P. Zhang et al., 2017a;, cervical cancer (Pathak et al., 2014;Pillai et al., 2003), and metastatic non-small-cell lung cancer (Y. Liu et al., 2015). ...
A lot of evidence has been found on the link between tumorigenesis and the aberrant expression of splicing factors. A number of splicing factors have been reported to be either oncogenic or overexpressed in cancer cells. However, splicing factors can also play negative roles in tumorigenesis. In the current review, we focus on splicing factor poly(rC)‐binding protein 1 (PCBP1), a novel tumor suppressor that is characterized by downregulation in many cancer types and shows inhibition of tumor formation and metastasis. Notably, the messenger RNA levels of PCBP1 are not significantly decreased in most cancer types. In fact, PCBP1 protein is often degraded or shows a loss‐of‐function through phosphorylation in cancer cells. PCBP1 is highly homologous to its family member, PCBP2. Interestingly, PCBP2 appears to be an oncogenic splicing factor. A growing body of evidence has shown that PCBP1 regulates alternative splicing, translation, and RNA stability of many cancer‐related genes. Taking together, PCBP1 has distinctive tumor suppressive functions, and increasing PCBP1 expression may represent a new approach for cancer treatment.
... The DNA methylation machinery induces 2 of 12 histone modifications and chromatin remodeling activities that act cooperatively in transcription regulation [2,3]. Several studies have highlighted the association between folate deficiency and an increasing incidence of certain types of malignancies, including human papilloma virus (HPV)-induced cervical cancer [4][5][6][7][8][9]. The mechanisms of how the folate status, especially a low folate status, contributes to these diseases remain unclear. ...
Folate is an essential water-soluble vitamin in food and nutrition supplements. As a one-carbon source, it is involved in many central regulatory processes, such as DNA, RNA, and protein methylation as well as DNA synthesis and repair. Deficiency in folate is considered to be associated with an increased incidence of several malignancies, including cervical cancer that is etiologically linked to an infection with “high-risk” human papilloma viruses (HPV). However, it is still not known how a recommended increase in dietary folate after its deprivation affects the physiological status of cells. To study the impact of folate depletion and its subsequent reconstitution in single cells, we used quantitative chromatin conformation measurements obtained by super-resolution fluorescence microscopy, i.e., single molecule localization microscopy (SMLM). As a read-out, we examined the levels and the (re)positioning of γ-H2AX tags and histone H3K9me3 heterochromatin tags after immunostaining in three-dimensional (3D)-conserved cell nuclei. As model, we used HPV16 positive immortalized human keratinocytes that were cultivated under normal, folate deficient, and reconstituted conditions for different periods of time. The results were compared to cells continuously cultivated in standard folate medium. After 13 weeks in low folate, an increase in the phosphorylation of the histone H2AX was noted, indicative of an accumulation of DNA double strand breaks. DNA repair activity represented by the formation of those γ-H2AX clusters was maintained during the following 15 weeks of examination. However, the clustered arrangements of tags appeared to relax in a time-dependent manner. Parallel to the repair activity, the chromatin methylation activity increased as detected by H3K9me3 tags. The progress of DNA double strand repair was accompanied by a reduction of the detected nucleosome density around the γ-H2AX clusters, suggesting a shift from hetero- to euchromatin to allow access to the repair machinery. In conclusion, these data demonstrated a folate-dependent repair activity and chromatin re-organization on the SMLM nanoscale level. This offers new opportunities to further investigate folate-induced chromatin re-organization and the associated mechanisms.
