Journal of Oncology Research and Therapy (ISSN: 2574-710X)

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DNA Methylation Studies and Molecular Therapy of Helicobacter pylori Strain for the Treatment of Gastric Cancer

Dowluru SVGK Kaladhar*

Department of Microbiology and Bioinformatics, UTD, Atal Bihari Vajpayee University, Bilaspur, Chhattisgarh, India

*Corresponding author: Dowluru SVGK Kaladhar, Department of Microbiology and Bioinformatics, UTD, Atal Bihari Vajpayee University, Bilaspur, Chhattisgarh, India

Received Date: 23 July, 2021 Accepted Date: 03 August, 2021 Published Date: 10 August, 2021

Citation: Kaladhar DSVGK. (2021) DNA Methylation Studies and Molecular Therapy of Helicobacter pylori Strain for the Treatment of Gastric Cancer. J Oncol Res Ther 6: 10106. DOI: https://doi.org/10.29011/2574-710X.010106

Abstract

DNA methylation is a cellular process in which DNA methyltransferase regulates in addition of a methyl group to DNA, which is an epigenetic and heritable alteration that leads to cancer. About 62 genes are reported as methylated as per SCDb database and based on analysis, CDH1 (Cadherin 1) gene is showing a good characteristic relationship with gastric cancer that is caused by Helicobacter pylori. The Methylation frequency above 50 is shown in genes like APC, BRCA1, DAPK1, and RARB. Tissue-specific circular RNA induction in the human fetal development is increased from 10 week to 20 week gradually due to the genes like CDH1, PTEN, HLA-B and TIMP3. Due to CDH1 gene mutation, Beta–catenin suppresses the T-cell responses and promotes the development of tumors due to H. pylori infection. The selected molecules like Pravastatin, Clopidogrel, Magnesium Sulfate and Nicotine have shown control of mutated APC and CDH1 proteins. The Pravastatin has shown best activity mutated APC and CDH1 proteins. Magnesium Sulfate has shown least activity in control of CDH1 and APC proteins. Hence the present work confirms that Pravastatin is the best option for the molecular therapy in control of gastric cancer followed by drugs like Clopidogrel, Nicotine and Magnesium Sulfate.

Keywords

Gastric cancer; DNA methylation; H. pylori; Molecular therapy

Introduction

Gastric cancer (also known as stomach cancer) is a disease that can affect the stomach due to growth of cancerous cells in the inner lining of the stomach [1,2]. An abnormal and uncontrolled cell growth in the stomach will be observed due to gastric cancer. The symptoms may include heartburn, blood in stool, indigestion, jaundice, or trouble in swallowing nausea, vomiting, weight loss, difficulty in swallowing, loss of appetite, whites of the eyes, yellowing of the skin, upper abdominal pain and blood in the stool [3,4].

The stomach is an organ that is present between the esophagus and the small intestine. Gastric cancer is mostly affects in older people having over the age of 45 years [5]. The risk of gastric cancer is due to having Helicobacter pylori infection in the stomach. Most of the genetic changes (mutations) are identified in some subset of humans affected by stomach cancer due to changes in environment and lifestyle [6]. Most of the gastric cancer cases are observed due to induced by Helicobacter pylori infection and the other causes include eating pickled vegetables, salted and smoked foods, drinking alcohol, cigarettes smoking, and genetic syndromes [7]. The treatment options include chemotherapy, surgery, radiation or a combination, and/or targeted therapy (such as monoclonal antibody therapy) [8]. The drugs Clopidogrel and Pravastatin are mostly using in the treatment of gastric cancer [9,10].

Helicobacter pylori (H. pylori :plural; H. pylorus: singular; Synonym: Campylobacter pylori) is a microaerophilic, gram-negative, spiral shaped bacterium with about 3 μm long and 0.5 μm diameter [11]. H. pylori will be found in the stomach that causes ulcers or gastritis (stomach inflammation). In the natural stomach ecology, H. pylorus plays a major role in influencing the other types of gastrointestinal probiotic bacteria like lactobacillus, Befidobacterium etc, which increase the levels of COX2 [12]. The probiotic bacteria trigger’s Helicobacter cysteine-rich proteins (Hcp), particularly HcpA (hp0211), increased genes like vacuolating toxin A (VacA) and the cytotoxin-associated gene A (CagA), tyrosine residues of host cell membrane-associated tyrosine kinase (TK), activation of protein tyrosine phosphatase/ protooncogene Shp2 and epidermal growth factor receptor (EGFR), high levels of TNF-α and/or interleukin 6 (IL-6), reduced protein expression of some of the DNA repair proteins like MLH1, MGMT and MRE11 that may be involved in gastric cancer [13].

A tumor suppressor gene produces proteins within the system that helps in regulation of cell division. Due to mutation in tumor suppressor gene like APC and CDH1, uncontrolled cell growth or apoptosis occurs and may lead to tumors [14].

Materials and Methods

Pubmeth

Pubmeth is a cancer methylation databased that is annotated and reviewed based on automated textmining of literature. The database includes reporting of genes that are methylated in several cancer types like Gastric cancer. The website for search for PUBMETH is http://pubmeth.biobix.be/search.html. The diseases that are related to Gastric cancer have been analyzed using pubmeth database.

SCDb

A comprehensive resource for the human Stomach Cancer database is SCDb. SCDb serves as search engines for Browse, Query, Summary and tools to know information of genes that are related to stomach cancer. The available website of SCDb is http:// www.stomachcancerdb.org/dblist/query. The Gene expression levels can be quantified using RPKM (Reads Per kilobase per Million mapped reads) method from SCDb.

KEGG / Kyoto Encyclopedia of Genes & Genomes Pathway Maps

The KEGG (Kyoto Encyclopedia of Genes & Genomes) Pathway database is a collection of graphical diagrams (KEGG pathway maps) and associated text information (KEGG pathway entries) for metabolism, various other cellular processes, and human diseases.

String v11.0

STRING v11.0 is a database that is know to predicted protein-protein interactions based on physical and functional associations from databases. The search site for multiple protein interactions is https://string-db.org/cgi/ input?sessionId=byDwXWOC0ymQ&input_page_active_ form=multiple_identifiers.

Retrieval/ Design of ligands and proteins

Molecules are visualized from Chemical Entities of Biological Interest (ChEBI) (https://www.ebi.ac.uk/chebi/ searchId.do?chebiId=63618) (Table 1). The molecules are designed using ChemSketch from ACDLabs v10.2 and was saved as .mol file format.

iGEMDOCKv2.1

iGEMDOCK v2.1 is a graphical environment that is used for recognizing pharmacological interactions and for conducting virtual screening for ligands with selected proteins. The tool is available at http://gemdock.life.nctu.edu.tw/dock/download.php.

Results and Discussion

There are 9990 genes that are involved in Human Gastric Cancer out of which 62 genes are reported as methylated genes. The 62 genes that are reported as methylated as per SCDb database are ALDH1A3, ANXA5, APC, AREG, BCL2L10, BNIP3, BRCA1, CCND2, CDH1, CDH2, CDKN2A, CDX2, CLDN3, DAB2IP, DAPK1, DKK1, DNAJC15, ESR1, F2R, FADS1, FHIT, FYN, GSTP1, HLA-B, HLTF, ID4, IGFBP3, IGFBP7, INSIG1, LOX, LZTS1, MLF1, MLH1, MTSS1, MX1, NID1, NID2, NT5E, PAX6, PGR, PPIC, PTEN, PTGS2, PYCARD, RAB32, RARB, RASSF2, RB1, RBP1, RBP4, RGS2, RPRM, SCRN1, SNAI1, SYK, TFAP2C, THBD, THBS1, TIMP3, TNFSF9, WIF1 and FGFR2. The information has been retrieved from Genecards (https://www.genecards.org/) (Table 2).

Table 2 has shown that CDH1 (Cadherin 1) is showing characteristic relationship with gastric cancer.

Table 3 has shown that Methylation frequency above 50 is shown for APC, BRCA1, CDH1, DAPK1 and RARB.

Table 4 and Figure 1 have shown that CDH1 is related to several diseases related to gastric cancer.

Table 5 has shown that Tissue-specific circular RNA induction during human fetal development has been increased from 10week to 20 week gradually due to CDH1, HLA-B, PTEN and TIMP3.

Figure 2 has shown that CDH1 is related to several other cancer causing genes like PTEN, BRCA1, MLH1, APC etc.

Figure 3 has shown that CDH1 acts on Beta-catenin that is important in transcription of Wnt-specific genes. Due to CDH1 gene mutation, Beta –catenin suppresses T-cell responses and promotes the progression of tumors.

The selected molecules like Clopidogrel, Pravastatin, Magnesium Sulfate and Nicotine have shown control of mutated CDH1 and APC proteins. The Pravastatin has shown best activity and Magnesium Sulfate has shown least activity in control of CDH1 and APC proteins. Hence Pravastatin is the best option molecular therapy in control of gastric cancer followed by Clopidogrel, Nicotine and Magnesium Sulfate (Table 6). Figure 4 and 5 has shown the docking poses and active site of drugs against CDH1 and APC proteins respectively.

DNA methylation is an epigenetic mechanism that is most favorable eukaryotes, an important regulator of the gene transcription and play key role in carcinogenesis [15-18]. Alterations in the process of DNA methylation are common in the development of a wide variety of tumors. Helicobacter pylori (H. pylori) infection can induce epigenetic changes and involve most important risk factor for the development of gastric cancer [19]. Chemoprevention with pravastatin may be important in molecular therapy of gastric cancer.

Conclusion

Due to CDH1 gene mutation, Beta–catenin suppresses the T-cell responses and promotes the progression of tumors due to H.pylori infection. The Pravastatin has shown best activity and Magnesium Sulfate has shown least activity in control of CDH1 and APC proteins. Hence Pravastatin is the best option molecular therapy in control of gastric cancer followed by Clopidogrel, Nicotine and Magnesium Sulfate.

Acknowledgements

The author likes to thank administration of Atal Bihari Vajpayee University for providing assistance and support.

Disclosure statement

The authors declare no conflicts of interest.


Figure 1: Graphical network of the top 7 diseases related to Gastric Cancer.




Figure 2: Protein-Protein interaction analysis.




Figure 3: Mechanism of CDH1 in Gastric cancer.


 

Figure 4: Docking of molecules with CDH1 protein.



Figure 5: Docking of molecules with APC protein.

S.No

Name

ChEBI

PubChem Id

1

Clopidogrel

CHEBI:37941

60606

2

Pravastatin

CHEBI:63618

54687

3

Magnesium Sulfate

CHEBI:32599

24083

4

(S)-Nicotine

CHEBI:17688

89594


Table 1: Drugs for Gastric Cancer (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB).
The mutated protein of tumor suppressor gene APC is retrieved from PDB database (https://www.rcsb.org/)

Methylated Gene

Name as on Gene Cards

Entrez Gene Summary

ALDH1A3

Aldehyde dehydrogenase enzyme

Associated with microphthalmia; detected in tumor cells

ANXA5

Annexin 5 gene

Implicated in many obstetric complications

APC

Adenomatosis Polyposis Coli

Colorectal cancers

AREG

Amphiregulin

Various types of cancers and inflammatory conditions

BCL2L10

BCL2 Like 10

Involved in many cellular activities like anti- or pro-apoptotic regulators

BNIP3

BCL2 Interacting Protein 3

Silenced in tumors by DNA methylation

BRCA1

Breast And Ovarian Cancer Susceptibility Protein 1

Modulating the subcellular localization; disease-associated mutations; transcription; recombination; DNA repair of double-stranded breaks

CCND2

Cyclin D2

Cell cycle G1/S transition; germ cell proliferation; ovarian and testicular tumors; megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 

CDH1

Cadherin 1

Gastric, colorectal, breast, thyroid and ovarian cancer.

CDH2

Cadherin 2

Development of the nervous system; establishment of left-right asymmetry; formation of cartilage and bone. 

CDKN2A

Cyclin Dependent Kinase Inhibitor 2A

Cell cycle G1 control; mutated or deleted in a wide variety of tumors; tumor suppressor gene

CDX2

Caudal Type Homeobox 2

Major regulator of intestine-specific genes; plays a major role in the early embryonic development of the intestinal tract.; associated with intestinal inflammation and tumorigenesis

CLDN3

Claudin 3

An integral membrane protein; component of tight junction strands; putative apoptosis-related protein

DAB2IP

Disabled Homolog 2-Interacting Protein

Tumor suppressor; inactivated by methylation in prostate and breast cancers

DAPK1

Death Associated Protein Kinase 1

Programmed cell death; a tumor suppressor candidate; splicing results in multiple transcript variants

DKK1

Dickkopf WNT Signaling Pathway Inhibitor 1

Role in embryonic development; important in bone formation in adults; Elevated expression causes numerous human cancers; promote proliferation, invasion and growth in cancer cell lines

DNAJC15

DnaJ Heat Shock Protein Family (Hsp40) Member C15

Protein Coding gene; Cause of 3-methylglutaconic aciduria type 5; dilated cardiomyopathy with ataxia; multiple transcript variants

ESR1

Estrogen Receptor 1

Central DNA binding domain; role in growth, metabolism, sexual development, gestation, and other reproductive functions; breast cancer, endometrial cancer, and osteoporosis; have dozens of transcript variants

F2R

Coagulation Factor II Thrombin Receptor

Regulation of thrombotic response; multiple transcript variants

FADS1

Fatty Acid Desaturase 1

Conserved histidine motifs; regulate unsaturation of fatty acids 

FHIT

Fragile Histidine Triad Diadenosine Triphosphatase

Involved in purine metabolism; carcinogen-induced damage; found in all esophageal, stomach, and colon carcinomas; tumor suppressor; loss of activity results in replication stress and DNA damage.

FYN

FYN Proto-Oncogene, Src Family Tyrosine Kinase

Protein-tyrosine kinase oncogene family;  implicated in the control of cell growth; existence of distinct isoforms

GSTP1

Glutathione S-Transferase Pi 1

Function in xenobiotic metabolism;  play a role in susceptibility to cancer and other diseases 

HLA-B

Major Histocompatibility Complex, Class I, B

Central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen;

HLTF

Helicase Like Transcription Factor

 Helicase and ATPase activities; regulate transcription 

ID4

Inhibitor Of DNA Binding 4, HLH Protein

Regulation of diverse cellular processes; development and tumorigenesis.

IGFBP3

Insulin Like Growth Factor Binding Protein 3

Transcriptional splice variants ;  altering interaction with cell surface receptors

IGFBP7

Insulin Like Growth Factor Binding Protein 7

Stimulates prostacyclin production and cell adhesion; associated with retinal arterial macroaneurysm

INSIG1

Insulin Induced Gene 1

Regulates cholesterol metabolism, lipogenesis, and glucose homeostasis; ubiquitin-mediated degradation; multiple transcript variants

LOX

Lysyl Oxidase

Multiple transcript variants; crosslinking of collagens and elastin; role in tumor suppression; predisposition to thoracic aortic aneurysms and dissections

LZTS1

Leucine Zipper Tumor Suppressor 1

Tumor suppressor protein; protein is silenced in rapidly metastasizing and metastatic tumor cells; role in cell-cycle control; Loss of heterozygosity (LOH) in the 8p arm is a common characteristic of many types of cancer.

MLF1

Myeloid Leukemia Factor 1

Phenotypic determination of hemopoetic cells; associated with myelodysplastic syndrome and acute myeloid leukemia; Multiple transcript variants 

MLH1

MutL Homolog 1

DNA mismatch repair system; involved in meiosis; hereditary nonpolyposis colon cancer 

MTSS1

MTSS I-BAR Domain Containing 1

Associated with Lung Giant Cell Carcinoma and Oropharyngeal Anthrax; identical protein binding and actin binding

MX1

MX Dynamin Like GTPase 1

Participates in the cellular antiviral response; multiple transcript variants

NID1

Nidogen 1

Basement membrane glycoproteins; role in cell interactions with the extracellular matrix

NID2

Nidogen 2

Basement membrane proteins; maintaining the structure of the basement membrane

NT5E

5'-Nucleotidase Ecto

Determinant of lymphocyte differentiation; Defects can lead to the calcification of joints and arteries

PAX6

Paired Box 6

Bind DNA and function as regulators of gene transcription; multiple transcript variants 

PGR

Progesterone Receptor

Central role in reproductive events associated with the organization and maintenance of pregnancy; mediates the physiological effects of progesterone

PPIC

Peptidylprolyl Isomerase C

Accelerate the folding of proteins; can bind immunosuppressant cyclosporin A

PTEN

Phosphatase And Tensin Homolog

Tumor suppressor that is mutated in many types of cancers at high frequency; multiple transcript variants

PTGS2

Prostaglandin-Endoperoxide Synthase 2

Enzyme in prostaglandin biosynthesis; involved in inflammation and mitogenesis

PYCARD

PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD).

Large signaling complexes in the inflammatory;  undergoing apoptosis

RAB32

RAB32, Member RAS Oncogene Family

Involved in autophagy; melanosome secretion; linked to leprosy

RARB

Retinoic Acid Receptor Beta

Mediates cellular signalling in embryonic morphogenesis;  cell growth;  differentiation; hepatocellular carcinoma; flanks a hepatitis B virus integration site; multiple transcript variants

RASSF2

Ras Association Domain Family Member 2

Located near the prion gene; Ras association

RB1

Retinoblastoma-Associated Protein

First tumor suppressor gene found; cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma

RBP1

Retinol Binding Protein 1

Necessary for growth, reproduction, differentiation of epithelial tissues and vision; Multiple transcript variants

RBP4

Retinol Binding Protein 4

Carrier for retinol (vitamin A alcohol) in the blood; prevents its loss by filtration through the kidney glomeruli; deficiency of vitamin A blocks secretion of the binding protein posttranslationally; deficiency results in defective delivery and supply to the epidermal cells

RGS2

Regulator Of G Protein Signaling 2

Mediator of myeloid differentiation;  play a role in leukemogenesis

RPRM

Reprimo, TP53 Dependent G2 Arrest Mediator Homolog

Related pathways are DNA Damage Response

SCRN1

Secernin 1

Regulation of exocytosis in mast cells; spliced transcript variants

SNAI1

Snail Family Transcriptional Repressor 1

Zinc finger transcriptional repressor ; critical for mesoderm formation in the developing embryo; downregulates the expression of ectodermal genes within the mesoderm; 

SYK

Spleen Associated Tyrosine Kinase

Widely expressed in hematopoietic cells; mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis; potential tumor suppressor in human breast carcinomas; spliced transcript variants

TFAP2C

Transcription Factor AP-2 Gamma

Activation of several developmental genes; induced during retinoic acid-mediated differentiation; plays a role in the development of the eyes, face, body wall, limbs, and neural tube

THBD

Thrombomodulin

Activation of protein C, which degrades clotting factors Va and VIIIa and reduces the amount of thrombin generated.; mutation cause of thromboembolic disease, also known as inherited thrombophilia.

THBS1

Thrombospondin 1

An adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions; play roles in platelet aggregation, angiogenesis, and tumorigenesis.

TIMP3

TIMP Metallopeptidase Inhibitor 3

Inhibitors of the matrix metalloproteinases; mutations cause autosomal dominant disorder Sorsby's fundus dystrophy; induced in response to mitogenic stimulation

TNFSF9

TNF Superfamily Member 9

Bidirectional signal transducer; generation of cytotoxic T cells; expressed in carcinoma cell lines,

WIF1

WNT Inhibitory Factor 1

Play a role in embryonic development; involved in mesoderm segmentation; epigenetically silenced in various cancers

FGFR2

Fibroblast Growth Factor Receptor 2

Interacts with fibroblast growth factors; influence mitogenesis and differentiation; associated with Crouzon syndrome, Craniosynostosis, Pfeiffer syndrome, Saethre-Chotzen syndrome,  Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, and syndromic craniosynostosis; Multiple alternatively spliced transcript variants


Table 2: Genes related to gastric cancer with methylation and its summary from Genecards.

Gene

Number of references

Number of references in gastric cancer

Number of samples

Methylation frequency

Details for methylation

In Gastric

ALDH1A3

1

1

10

20

no subtype specified (1)

ANXA5

--

--

--

--

-

APC

65

7

343

59

adenoma (2); adenocarcinoma (2); no subtype specified (2); Soft tissue sarcoma (1)

AREG

1

1

10

10

no subtype specified (1)

BCL2L10

--

--

--

--

--

BNIP3

3

--

--

--

--

BRCA1

16

1

83

55

no subtype specified (1)

CCND2

9

--

--

--

--

CDH1

81

13

597

52

carcinoma (8); no subtype specified (2); adenocarcinoma (1); adenoma (1); soft tissue sarcoma (1)

CDH2

1

--

--

--

--

CDKN2A

205

21

1433

30

no subtype specified (8); carcinoma (6); adenocarcinoma (3); adenoma (3); soft tissue sarcoma (1)

CDX2

2

1

73

29

no subtype specified (1)

CLDN3

--

--

--

--

--

DAB2IP

--

--

--

--

--

DAPK1

 

68

7

660

51

adenoma (3), no subtype specified (3), carcinoma (1)

DKK1

1

1

0

0

no subtype specified (1)

DNAJC15

1

1

10

30

neuroectodermal tumour (1)

ESR1

24

1

0

0

no subtype specified (1)

F2R

1

1

10

20

no subtype specified (1)

FADS1

-

--

--

--

--

FHIT

24

--

--

--

--

FYN

--

--

--

--

--

GSTP1

56

3

200

7

adenoma (1); carcinoma (1); no subtype specified (1)

HLA-B

1

1

60

40

no subtype specified (1)

HLTF

4

1

46

20

no subtype specified (1)

 

ID4

4

1

76

30

adenocarcinoma (1)

IGFBP3

8

--

--

--

--

IGFBP7

2

--

--

--

--

INSIG1

1

1

22

50

no subtype specified (1)

LOX

--

--

--

--

--

LZTS1

--

--

--

--

--

MLF1

--

--

--

--

--

MLH1

69

21

1154

22

carcinoma (10); no subtype specified (5); adenocarcinoma (3); adenoma (2); intestinal (1)

MTSS1

--

--

--

--

--

MX1

--

--

--

--

--

NID1

--

--

--

--

--

NID2

--

--

--

--

--

NT5E

--

--

--

--

--

PAX6

1

--

--

--

--

PGR

6

--

--

--

--

PPIC

--

--

--

--

--

PTEN

15

1

66

39

carcinoma (1)

PTGS2

20

7

653

19

carcinoma (3); no subtype specified (3); adenoma (1)

PYCARD

9

1

10

0

no subtype specified (1)

RAB32

1

1

48

27

adenocarcinoma (1)

RARB

48

4

246

51

carcinoma (2); no subtype specified (2)

RASSF2

1

--

--

--

--

RB1

15

--

--

--

--

RBP1

2

--

--

--

--

RBP4

--

--

--

--

--

RGS2

1

1

10

0

no subtype specified (1)

RPRM

8

1

0

0

no subtype specified (1)

SCRN1

--

--

--

--

--

SNAI1

1

1

10

0

no subtype specified (1)

 

SYK

8

2

61

34

carcinoma (1); no subtype specified (1)

TFAP2C

--

--

--

--

--

THBD

--

--

--

--

--

THBS1

19

6

625

38

no subtype specified (3); carcinoma (2); adenoma (1)

TIMP3

34

4

254

25

adenoma (3); no subtype specified (1)

TNFSF9

--

--

--

--

--

WIF1

8

--

--

--

--

FGFR2

--

--

--

--

--


Table 3: methylated frequency and detils in Gastric cancer genes using Pubmeth.

S.No

Related Disease

Top Affiliating Genes (text searches by Pubmeth)

1

Sarcoma

APC, CDH1, CDKN2A, DAPK1

2

Adenoma

APC, CDH1, CDKN2A, DAPK1 , GSTP1, MLH1, PTGS2, THBS1, TIMP3

3

Neuroectodermal tumour

DNAJC15

4

Adenocarcinoma

APC, CDH1, CDKN2A, ID4, MLH1, RAB32, ID4

5

Carcinoma

CDH1, CDKN2A, GSTP1, MLH1, PTEN, PTGS2, RARB, SYK, THBS1

6

Intestinal

MLH1

7

No subtype specified

ALDH1A3, APC, AREG, BRCA1, CDH1, CDKN2A, CDX2, DAPK1 , DKK1, ESR1, F2R, GSTP1, HLA-B, HLTF, NSIG1, MLH1, PTGS2, PYCARD, RARB, RGS2, RPRM, SNAI1, SYK, THBS1, TIMP3


Table 4:  Diseases related to Gastric Cancer.

Gene

Methylation frequency

Reads Per Kilobase of transcript, per Million mapped reads (RPKM)

HPA RNA-seq normal tissues

RNA sequencing of total RNA from 20 human tissues

Tissue-specific circular RNA induction during human fetal development

 

10Wk

16WK

18 wk

20Wk

ALDH1A3

20

6.493± 2.886

1.571

1.339±0.081

2.585

1.949

3.325 ± 0.504

APC

59

2.171 ± 0.773

1.521

4.506±0.49

6.645

6.024

5.741±0.485

AREG

10

8.789±4.535

0.942

0.017±0.017

0.041

0.026

0.03±0.025

BRCA1

55

0.869±0.342

0.445

1.771±0.082

1.591

1.755

1.783±0.173

CDH1

52

49.374±13.587

13.78

9.971±0.239

18.684

18.918

18.719±0.886

CDKN2A

30

0.344±0.347

0.042

0.01±0.001

0.012

0

0.015±0.021

CDX2

29

0

0.091

0.215±0.215

0

0.085

0

DAPK1

51

7.785±2.725

2.608

6.396±0.123

6.713

6.067

6.288±0.184

DNAJC15

30

5.177±1.071

2.408

2.767±0.01

4.014

5.941

5.12±0.65

F2R

20

5.02±0.927

1.867

5.496±0.098

5.181

6.161

5.509±0.637

GSTP1

7

173.829±89.126

37.927

21.165±8.309

33.007

61.985

48.063±6.079

HLA-B

40

269.516±86.645

36.153

3.013±1.096

6.595

8.141

14.092±9.148

HLTF

20

4.47±1.498

1.457

4.334±0.426

5.186

5.527

5.13±0.415

ID4

30

8.625±5.243

1.802

5.459±0.884

7.885

10.285

9.941±0.693

INSIG1

50

17.359±1.653

4.373

2.492±0.185

6.034

8.679

5.683±0.157

MLH1

22

5.409±0.706

2.826

4.326±0.235

5.227

5.89

5.68±0.526

PTEN

39

8.303±1.828

3.666

6.643±0.678

11.059

11.206

11.494±0.971

PTGS2

19

1.905±1.847

1.158

0.599±0.084

1.136

3.143

1.986±0.983

RAB32

27

6.901±1.864

1.066

1.934±0.385

2.3

3.832

3.441±0.61

RARB

51

1.228±0.535

0.828

3.651±0.649

5.523

6.791

4.949±1.07

SYK

34

9.23±1.112

3.317

2.41±0.271

2.485

4.019

3.064±0.169

THBS1

38

22.886±16.861

11.345

13.62±1.188

23.401

28.878

21.43±0.933

TIMP3

25

19.121±2.647

16.301

14.244±2.006

30.908

32.44

35.32±5.48


Table 5: Million mapped reads (RPKM) for Gastric cancer genes.

S.No

Name of Drug

APC

CDH1

 

Total energy in Kcal/mol

Active site

Total energy in Kcal/mol

Active site

1

Clopidogrel

-72.66

V-M-LEU-37-V-M-GLU-40-V-S-GLU-40-V-M-ALA-41-V-S-MET-44-V-M-ALA-41-V-S-MET-44

-63.8

H-S-GLN-23-V-M-PRO-5 -V-S-PRO-6-V-S-LYS-73-V-M-GLN-23-V-S-GLN-23

 

 

 

 

 

2

Pravastatin

-92.21

H-S-ASN-22-H-S-GLU-26-H-M-LEU-27-V-S-GLU-19-V-S-LEU-23-V-S-GLU-26-V-S-ASN-30-V-M-LEU-27-V-S-LEU-27-V-M-GLU-28-V-S-GLU-28

-94.32

H-M-VAL-3-H-S-THR-97-H-M-GLN-23-H-M-LYS-25-V-S-VAL-3-V-M-ILE-4-V-M-PRO-5-V-S-PRO-6-V-S-LYS-73-V-S-VAL-95-V-S-THR-97-V-S-GLN-23-V-S-LYS-25

3

Magnesium Sulfate

-39.85

H-S-ASN-20-H-S-ARG-24-V-S-LYS-17

-36.23

H-M-VAL-3-H-M-GLU-93

 

 

 

 

 

4

Nicotine

-57.33

H-M-LEU-37-H-S-GLU-40-V-M-GLU-40-V-S-GLU-40-V-M-ALA-41-V-M-ALA-41-V-S-MET-44

-51.95

H-M-VAL-3-H-M-ILE-4-H-M-GLN-23-V-S-VAL-3-V-M-ILE-4-V-S-PRO-6-V-S-VAL-95-V-S-GLN-23


Table 6: Activity of drugs against CDH1 gene as molecular therapy for Gastric cancer.

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