Publications by authors named "Samatha Bhat"

14 Publications

  • Page 1 of 1

Optimization of culture conditions for human bone marrow-derived mesenchymal stromal cell expansion in macrocarrier-based Tide Motion system.

Biotechnol J 2021 Jul 25;16(7):e2000540. Epub 2021 Apr 25.

Stempeutics Research Pvt Ltd, Shirdi Sai Baba Cancer Hospital, Manipal, Karnataka, India.

Background: With high cell doses required for mesenchymal stromal cell (MSC) clinical trials, there is a need to upgrade technologies that facilitate efficient scale up of MSCs for cell therapy. Conventional expansion with 2D culture vessels becomes the bottleneck when large cell dosages are required. Tide Motion bioreactors offer a robust, scalable platform using BioNOC II macrocarriers developed for the production of adherent cells.

Methods: We evaluated the growth and expansion of bone marrow-derived MSCs (BM-MSCs) on the macrocarrier-based culture system by optimizing key parameters such as cell seeding densities, culturing conditions, and harvesting procedures to achieve optimal cell growth. BM-MSCs expanded in conventional 2D adherent cultures were seeded into BioNOC II macrocarriers and grown in serum-containing or serum-free medium.

Results: BM-MSCs attained a maximum cell density of 0.49 ± 0.07 × 10 cells/carrier after 12 days of culture in BioNOC II macrocarriers with cell viability > 86% while retaining MSC specific characteristics such as surface marker expression, tri-lineage differentiation potential, immunosuppressive properties, and potency.

Conclusion: These results reveal the feasibility of BM-MSC expansion in the scalable macrocarrier-based Tide Motion system both under serum and serum-free conditions and represent an important step for the large-scale production system of BM-MSC based cellular therapies.
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http://dx.doi.org/10.1002/biot.202000540DOI Listing
July 2021

Novel bioactive formulation derived from the conditioned medium of mesenchymal stromal cells reduces under-eye dark circles in human volunteers.

J Cosmet Dermatol 2021 Apr 9. Epub 2021 Apr 9.

Stempeutics Research Pvt Ltd, Shirdi Sai Baba Cancer Hospital, Manipal, India.

Background: Under-eye dark circles are a common condition observed in dermatology practice. Mesenchymal stromal cell-derived conditioned medium (MSC-CM) contains an array of growth factors and cytokines reported to promote periorbital rejuvenation and may be useful in removing the dark circle around the eyes.

Aims: The aim of the present study was to evaluate the safety and efficacy of developed bioactive formulation containing mesenchymal stromal cell-derived conditioned medium in reducing the under-eye dark circles.

Patients/methods: We tested the safety profile of MSC-CM along with antioxidants, in vitro using human melanocytes cultures. The bioactive formulation containing MSC-CM was developed and tested for physicochemical parameters. The dermatological safety was evaluated by primary irritant patch-test under complete occlusion on healthy human subjects. To elucidate its safety and efficacy, monocentric, open-label, single-arm study was carried out in 20 Indian female subjects for the duration of 12 weeks. Parameters such as eye puffiness, radiance, skin smoothness, even skin tone, periorbital fine lines and wrinkles, crow's feet, whitening, pigmentation, skin tightening, and refreshing/soothing effect were used to investigate the rejuvenating property of the bioactive formulation.

Results: Mesenchymal stromal cell-derived conditioned medium along with antioxidants decreased the melanin content compared to the CM alone in the melanocyte cultures. Besides, the bioactive formulation was safe and emerged as a non-irritant product. Improvement in the majority of the clinical parameters assessed through efficacy study was observed within 4 weeks of topical application of the formulation twice daily, and showed continued improvement for 12 weeks as evaluated by the dermatologists as well as self-assessment by the subjects.

Conclusion: The bioactive formulation containing MSC-CM was safe and effective in reducing the under-eye dark circles and was beneficial in improving the overall appearance of the eye area.
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http://dx.doi.org/10.1111/jocd.14145DOI Listing
April 2021

Metastatic suppression by DOC2B is mediated by inhibition of epithelial-mesenchymal transition and induction of senescence.

Cell Biol Toxicol 2021 Mar 24. Epub 2021 Mar 24.

Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, 576104, India.

Senescence induction and epithelial-mesenchymal transition (EMT) events are the opposite sides of the spectrum of cancer phenotypes. The key molecules involved in these processes may get influenced or altered by genetic and epigenetic changes during tumor progression. Double C2-like domain beta (DOC2B), an intracellular vesicle trafficking protein of the double C2 protein family, plays a critical role in exocytosis, neurotransmitter release, and intracellular vesicle trafficking. DOC2B is repressed by DNA promoter hypermethylation and functions as a tumor growth regulator in cervical cancer. To date, the molecular mechanisms of DOC2B in cervical cancer progression and metastasis is elusive. Herein, the biological functions and molecular mechanisms regulated by DOC2B and its impact on senescence and EMT are described. DOC2B inhibition promotes proliferation, growth, and migration by relieving G0/G1-S arrest, actin remodeling, and anoikis resistance in Cal27 cells. It enhanced tumor growth and liver metastasis in nude mice with the concomitant increase in metastasis-associated CD55 and CD61 expression. Inhibition of EMT and promotion of senescence by DOC2B is a calcium-dependent process and accompanied by calcium-mediated interaction between DOC2B and CDH1. In addition, we have identified several EMT and senescence regulators as targets of DOC2B. We show that DOC2B may act as a metastatic suppressor by inhibiting EMT through induction of senescence via DOC2B-calcium-EMT-senescence axis.
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http://dx.doi.org/10.1007/s10565-021-09598-wDOI Listing
March 2021

ZNF471 modulates EMT and functions as methylation regulated tumor suppressor with diagnostic and prognostic significance in cervical cancer.

Cell Biol Toxicol 2021 10 10;37(5):731-749. Epub 2021 Feb 10.

Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.

Cervical cancer (CC) is a leading cause of cancer-related death among women in developing countries. However, the underlying mechanisms and molecular targets for therapy remain to be fully understood. We investigated the epigenetic regulation, biological functions, and clinical utility of zinc-finger protein 471 (ZNF471) in CC. Analysis of cervical tissues and five independent public datasets of CC showed significant hypermethylation of the ZNF471 gene promoter. In CC cell lines, promoter DNA methylation was inversely correlated with ZNF471 expression. The sensitivity and specificity of the ZNF471 hypermethylation for squamous intraepithelial lesion (SIL) vs tumor and normal vs tumor was above 85% with AUC of 0.937. High methylation and low ZNF471 expression predicted poor overall and recurrence-free survival. We identified -686 to +114 bp as ZNF471 promoter, regulated by methylation using transient transfection and luciferase assays. The promoter CpG site methylation of ZNF471 was significantly different among cancer types and tumor grades. Gal4-based heterologous luciferase reporter gene assays revealed that ZNF471 acts as a transcriptional repressor. The retroviral mediated overexpression of ZNF471 in SiHa and CaSki cells inhibited growth, proliferation, cell migration, invasion; delayed cell cycle progression in vitro by increasing cell doubling time; and reduced tumor growth in vivo in nude mice. ZNF471 overexpression inhibited key members of epithelial-mesenchymal transition (EMT), Wnt, and PI3K-AKT signaling pathways. ZNF471 inhibited EMT by directly targeting vimentin as analyzed by bioinformatic analysis, ChIP-PCR, and western blotting. Thus, ZNF471 CpG specific promoter methylation may determine the prognosis of CC and could function as a potential tumor suppressor by targeting EMT signaling.
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http://dx.doi.org/10.1007/s10565-021-09582-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490246PMC
October 2021

Expansion and characterization of bone marrow derived human mesenchymal stromal cells in serum-free conditions.

Sci Rep 2021 02 9;11(1):3403. Epub 2021 Feb 9.

Stempeutics Research Pvt Ltd, Shirdi Sai Baba Cancer Hospital, Manipal, Karnataka, 576104, India.

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are gaining increasing importance in the field of regenerative medicine. Although therapeutic value of MSCs is now being established through many clinical trials, issues have been raised regarding their expansion as per regulatory guidelines. Fetal bovine serum usage in cell therapy poses difficulties due to its less-defined, highly variable composition and safety issues. Hence, there is a need for transition from serum-based to serum-free media (SFM). Since SFM are cell type-specific, a precise analysis of the properties of MSCs cultured in SFM is required to determine the most suitable one. Six different commercially available low serum/SFM with two different seeding densities were evaluated to explore their ability to support the growth and expansion of BM-MSCs and assess the characteristics of BM-MSCs cultured in these media. Except for one of the SFM, all other media tested supported the growth of BM-MSCs at a low seeding density. No significant differences were observed in the expression of MSC specific markers among the various media tested. In contrary, the population doubling time, cell yield, potency, colony-forming ability, differentiation potential, and immunosuppressive properties of MSCs varied with one another. We show that SFM tested supports the growth and expansion of BM-MSCs even at low seeding density and may serve as possible replacement for animal-derived serum.
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http://dx.doi.org/10.1038/s41598-021-83088-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873235PMC
February 2021

A nanocomposite hydrogel delivery system for mesenchymal stromal cell secretome.

Stem Cell Res Ther 2020 05 27;11(1):205. Epub 2020 May 27.

Stempeutics Research Private Limited, Shirdi Sai Baba Cancer Hospital, Manipal, 576104, India.

Background: Mesenchymal stromal cell conditioned medium (MSC-CM) contains a cocktail of bioactive factors that act synergistically to induce therapeutic effects. This has been clearly demonstrated by in vivo applications of MSC-CM, but the establishment of controlled delivery systems is an unmet requirement for clinical translation.

Methods: We developed a nanocomposite-hydrogel (NP-H) comprised of poly-L-lactide nanoparticles (NPs) embedded in gelatin/hyaluronic acid (Gel/HA) hydrogel as a delivery vehicle for MSC-CM. First, we optimized the culture conditions for bone marrow-derived MSCs using serum-containing medium (SCM) and serum-free medium (SFM) and characterized the corresponding CM (serum-containing conditioned medium (ScCM) and serum-free conditioned medium (SfCM), respectively) for its potency and xeno markers. Then we prepared a composite matrix followed by physiochemical characterization and functional assays were performed.

Results: Nanocomposite hydrogel displayed an even distribution of NPs along with high porosity (> 60%) and swelling ratios > 1500%, while its protein release pattern corresponded to a mix of degradation and diffusion kinetics. Functional evaluation of the composites was determined using MSCs and human fibroblasts (HFFs). The cells seeded directly onto the composites displayed increasing metabolic activities over time, with ScCM-NP-H groups having maximum activity. The cells treated in vitro with 5% and 10% extracts of ScCM-NP-H and SfCM-NP-H exhibited a dose- and duration-dependent response. Cell activities reduced considerably for all groups, except 10% ScCM-NP-H, which displayed a significant increase over time.

Conclusion: We observed that sustained release of MSC-CM is required to prevent dose-dependent cytotoxicity. The proposed nanocomposite hydrogel for MSC-CM delivery can open up a new array for its clinical application.
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http://dx.doi.org/10.1186/s13287-020-01712-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251860PMC
May 2020

Aberrant gene-specific DNA methylation signature analysis in cervical cancer.

Tumour Biol 2017 Mar;39(3):1010428317694573

1 Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, India.

Multicomponent molecular modifications such as DNA methylation may offer sensitive and specific cervical intraepithelial neoplasia and cervical cancer biomarkers. In this study, we tested cervical tissues at various stages of tumor progression for 5-methylcytosine and 5-hydroxymethylcytosine levels and also DNA promoter methylation profile of a panel of genes for its diagnostic potential. In total, 5-methylcytosine, 5-hydroxymethylcytosine, and promoter methylation of 33 genes were evaluated by reversed-phase high-performance liquid chromatography, enzyme-linked immunosorbent assay based technique, and bisulfate-based next generation sequencing. The 5-methylcytosine and 5-hydroxymethylcytosine contents were significantly reduced in squamous cell carcinoma and receiver operating characteristic curve analysis showed a significant difference in (1) 5-methylcytosine between normal and squamous cell carcinoma tissues (area under the curve = 0.946) and (2) 5-hydroxymethylcytosine levels among normal, squamous intraepithelial lesions and squamous cell carcinoma. Analyses of our next generation sequencing results and data from five independent published studies consisting of 191 normal, 10 low-grade squamous intraepithelial lesions, 21 high-grade squamous intraepithelial lesions, and 335 malignant tissues identified a panel of nine genes ( ARHGAP6, DAPK1, HAND2, NKX2-2, NNAT, PCDH10, PROX1, PITX2, and RAB6C) which could effectively discriminate among the various groups with sensitivity and specificity of 80%-100% (p < 0.05). Furthermore, 12 gene promoters (ARHGAP6, HAND2, LHX9, HEY2, NKX2-2, PCDH10, PITX2, PROX1, TBX3, IKBKG, RAB6C, and DAPK1) were also methylated in one or more of the cervical cancer cell lines tested. The global and gene-specific methylation of the panel of genes identified in our study may serve as useful biomarkers for the early detection and clinical management of cervical cancer.
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http://dx.doi.org/10.1177/1010428317694573DOI Listing
March 2017

Gene promoter-associated CpG island hypermethylation in squamous cell carcinoma of the tongue.

Virchows Arch 2017 Apr 2;470(4):445-454. Epub 2017 Mar 2.

Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India.

The present study was undertaken to explore and validate novel hypermethylated DNA regions in squamous cell carcinoma of the tongue (SCCT). Genome-wide methylation changes were identified by differential methylation hybridization (DMH) microarray and validated by bisulfite genome sequencing (BGS). The results were compared against datasets from The Cancer Genome Atlas head and neck squamous cell carcinoma (TCGA-HNSCC), Gene Expression Omnibus (GSE26549), and ArrayExpress (E-MTAB-1328). DMH identified 116 hypomethylated and 241 hypermethylated regions. Of the latter, 24 were localized to promoter or 5'-UTR regions. By BGS, promoter sequences of DAPK1, LRPPRC, RAB6C, and ZNF471 were significantly hypermethylated in tumors when compared with matched normal tissues (P < 0.0001). A TCGA-HNSCC dataset (516 cases of cancer and 50 normal tissue samples) further confirmed hypermethylation of DAPK1, RAB6C, and ZNF471. Sensitivity and specificity of methylation markers for a diagnosis of cancer were in the range of 70-100% in our study and from TCGA-HNSCC datasets, with an area under curve (AUC) of 0.83 and above. Kaplan-Meier survival analysis of TCGA-HNSCC expression data revealed that patients with low expressions of DAPK1, RAB6C, and ZNF471 showed poorer survival than patients with high expression (P = 0.02). Human papillomavirus (HPV) was found in 55% of cases, HPV16 being the predominant genotype. DAPK1 immunohistochemical staining was lower in SCCT than in normal buccal epithelial cells. This is the first study to report hypermethylation of LRPPRC, RAB6C, and ZNF471 in SCCT and its diagnostic and prognostic potentials in a specific head and neck squamous cell carcinoma.
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http://dx.doi.org/10.1007/s00428-017-2094-2DOI Listing
April 2017

Cervical cytological abnormalities and human papilloma virus infection in women infected with HIV in Southern India.

J Obstet Gynaecol Res 2016 Dec 19;42(12):1822-1828. Epub 2016 Sep 19.

Department of Pediatrics, Wake Forest School of Medicine, Salem, North Carolina, USA.

Aim: The aim of this study was to examine the association between CD4 count, human papilloma virus (HPV) infection, and the risk of cervical intraepithelial neoplasia among HIV-infected women.

Methods: A cross-sectional study was conducted among 104 HIV-infected women attending an antiretroviral therapy clinic. They underwent Pap smear and cervical HPV DNA testing.

Results: The overall prevalence of HPV infection was 57.7%. HPV 16 was the commonest genotype found (38.5%); HPV 16 and 18 put together contributed to 73.3% of HPV infection; 27.5% of HIV-infected women had squamous cell abnormalities. Cervical intraepithelial neoplasia was less likely among women with CD4 count > 500/mm (12%) and in those without opportunistic infections (17.8%). The prevalence of high-risk HPV infection was higher in women with high-grade squamous intraepithelial lesions or greater lesions (85.7%) as compared to women with normal cytology (52.1%).

Conclusion: The high prevalence of HPV infection and cervical intraepithelial neoplasia in HIV-infected women warrants the need for regular Pap smear screening in these women and routine HPV vaccination for adolescents to reduce the burden of cervical cancer in India.
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http://dx.doi.org/10.1111/jog.13111DOI Listing
December 2016

Biological implications and therapeutic significance of DNA methylation regulated genes in cervical cancer.

Biochimie 2016 Feb 29;121:298-311. Epub 2015 Dec 29.

Department of Biotechnology, School of Life Sciences, Manipal University, Karnataka 576104, India. Electronic address:

Cervical cancer is the second most common cancer among women worldwide. About 528,000 women are diagnosed with cervical cancer contributing to around 266,000 deaths, across the globe every year. Out of these, the burden of 226,000 (85%) deaths occurs in the developing countries, who are less resource intensive to manage the disease. This is despite the fact that cervical cancer is amenable for early detection due to its long and relatively well-known natural history prior to its culmination as invasive disease. Infection with high risk human papillomavirus (hrHPVs) is essential but not sufficient to cause cervical cancer. Although it was thought that genetic mutations alone was sufficient to cause cervical cancer, the current epidemiological and molecular studies have shown that HPV infection along with genetic and epigenetic changes are frequently associated and essential for initiation, development and progression of the disease. Moreover, aberrant DNA methylation in host and HPV genome can be utilized not only as biomarkers for early detection, disease progression, diagnosis and prognosis of cervical cancer but also to design effective therapeutic strategies. In this review, we focus on recent studies on DNA methylation changes in cervical cancer and their potential role as biomarkers for early diagnosis, prognosis and targeted therapy.
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http://dx.doi.org/10.1016/j.biochi.2015.12.018DOI Listing
February 2016

Prevalence of human papillomavirus types and phylogenetic analysis of HPV-16 L1 variants from Southern India.

Asian Pac J Cancer Prev 2015 ;16(5):2073-80

Division of Biotechnology, School of Life Sciences, Manipal University, Karnataka, India E-mail :

Background: The human papillomavirus (HPV) and its variants show wide geographical distribution and have been reported to cause cervical lesions. With cervical neoplasia as the leading cancer in Indian women, the aim of the present study was to evaluate the multiple infection HPV type distribution and variant genotypes in cervical samples from the coastal Karnataka region, India.

Materials And Methods: A total of 212 samples were screened by nested polymerase chain reaction using PGMY9/11 and GP5+/6+ primers. HPV positive samples were sequenced to identify the types and a phylogenetic tree was constructed using the neighbor-joining method.

Results: Sequence analysis identified a total of 14 HPV types distributed in 20%, 73.3% and 82.5% of non-malignant, pre-malignant [low grade squamous intraepithelial lesion (LSIL) and high grade squamous intraepithelial lesion (HSIL)] and cervical cancer samples. The distribution of high risk HPV in cancer samples was HPV 16, 76.4%, HPV18, 11.7%, HPV81, 2.9%, HPV31, 1.4%, HPV35, 1.4% and HPV 45, 1.4%. Multiple infections were observed in 11.8% of tumor samples with HPV 16 contributing to 62.5% of cases. In non-malignant samples, 20% of HPV positive samples were detected with HPV16, 82.3%, HPV33, 5.8% and HPV58, 5.8% and very low incidence of multiple infections. Comparative phylogenetic analysis of HPV variants identified 9 HPV sequences as new papillomavirus species, predominantly classified as European lineage type.

Conclusions: The findings for HPV infections associated with progression of cervical cancer in coastal Karnataka region and HPV variant analysis provide baseline data for prevention and HPV vaccination programs.
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http://dx.doi.org/10.7314/apjcp.2015.16.5.2073DOI Listing
December 2015

Epigenetic regulation of double c2 like domain beta (Doc2b) in cervical cancer.

Mol Cytogenet 2014 21;7(Suppl 1 Proceedings of the International Conference on Human):I22. Epub 2014 Jan 21.

Manipal Life Sciences Center, Manipal University,Manipal, Karnataka, India.

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http://dx.doi.org/10.1186/1755-8166-7-S1-I22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4044774PMC
June 2014

DNA promoter methylation-dependent transcription of the double C2-like domain β (DOC2B) gene regulates tumor growth in human cervical cancer.

J Biol Chem 2014 Apr 25;289(15):10637-10649. Epub 2014 Feb 25.

Division of Biotechnology, Manipal Life Sciences Centre, Manipal University, Manipal 576104, India. Electronic address:

Double C2-like domain β (DOC2B) gene encodes for a calcium-binding protein, which is involved in neurotransmitter release, sorting, and exocytosis. We have identified the promoter region of the DOC2B gene as hypermethylated in pre-malignant, malignant cervical tissues, and cervical cancer cell lines by methylation-sensitive dimethyl sulfoxide-polymerase chain reaction and bisulfite genome sequencing; whereas, it was unmethylated in normal cervical tissues (p < 0.05). The promoter hypermethylation was inversely associated with mRNA expression in SiHa, CaSki, and HeLa cells and treatment with demethylating agent 5-aza-2-deoxycytidine restored DOC2B expression. The region -630 to +25 bp of the DOC2B gene showed robust promoter activity by a luciferase reporter assay and was inhibited by in vitro artificial methylation with Sss1 methylase prior to transient transfections. Overexpression of the DOC2B gene in SiHa cells when compared with controls showed significantly reduced colony formation, cell proliferation, induced cell cycle arrest, and repressed cell migration and invasion (p < 0.05). Ectopic expression of DOC2B resulted in anoikis-mediated cell death and repressed tumor growth in a nude mice xenograft model (p < 0.05). DOC2B expressing cells showed a significant increase in intracellular calcium level (p < 0.05), impaired AKT1 and ERK1/2 signaling, and induced actin cytoskeleton remodeling. Our results show that promoter hypermethylation and silencing of the DOC2B gene is an early and frequent event during cervical carcinogenesis and whose reduced expression due to DNA promoter methylation may lead to selective cervical tumor growth.
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http://dx.doi.org/10.1074/jbc.M113.491506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036182PMC
April 2014

Mitochondrial DNA variation analysis in cervical cancer.

Mitochondrion 2014 May 10;16:73-82. Epub 2013 Jul 10.

Division of Biotechnology, Manipal Life Sciences Centre, Manipal University, Manipal, Karnataka, India. Electronic address:

This study was undertaken to investigate the mitochondrial DNA (mtDNA) variation in non-malignant and malignant cervical tissue samples. We have identified 229 and 739 variations non-malignant and malignant tissues respectively distributed over 321 locations in the D-loop (50 in non-malignant and 166 in malignant; 216 variations), coding region (139 in non-malignant and 455 in malignant; 594 variations) tRNA and rRNA genes (39 in non-malignant and 119 in malignant; 158 variations). Besides, 77 novel and 34 various other disease associated variations were identified in non-malignant and malignant samples. A total of 236 tumor specific variations in 201 locations representing 30.1% in D-loop, 59.3% in coding regions and 10.6% in RNA genes were also identified. Our study shows that D loop (in 67 locations) is highly altered followed by ND5 (35 locations) region. Moreover, mtDNA alterations were significantly higher in malignant samples by two tailed Fisher's exact test (P≤0.05) with decreased mtDNA copy numbers. Bioinformatic analysis of 59 non-synonymous changes predicted several variations as damaging leading to decreased stability of the proteins. Taken together, mtDNA is highly altered in cervical cancer and functional studies are needed to be investigated to understand the consequence of these variations in cervical carcinogenesis and their potential application as biomarkers.
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http://dx.doi.org/10.1016/j.mito.2013.07.001DOI Listing
May 2014
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