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Computational Anti-Cancer Immune stimulation using Tumor Cell RNAs CAIS-TR

Manual Curation of miRNA networks and Network analysis

We have constructed a miRNA-disease network for colorectal cancer through mirnet [1] tool which integrates data from eleven other miRNA databases according to the latest update of exosomal and tissue-specific miRNAs. The constructed network [figure-1] has been analysed using cytoscape [2] for significant interaction according to the curated attributes of statistical significance. The analysis included curation of published evidence as filtering attribute in addition to statistical significance which suggested miRNAs (mir-134 and mir-370) to be of very significant connection to colorectal cancer network and by further literature research we found a potential tumor suppressor role for both RNA molecules in CRC carcinogenesis by regulating EGFR signaling cascade through targeting PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) and EGFR (Epidermal growth factor receptor) [3]. (Figure 1).

Figure 1: Colorectal cancer constructed network, analyzed using cytoscape

MiRNA-mRNA interaction networks String database [4] has been mined using RAIN tool [5] in order to construct interaction networks for both miRNAs (mir-370-3p and mir-134-5p) to be used for further pathway analysis [Figure-2, Figure-3].

Figure 2: String database interaction network of mir-134-5p and target proteins
Figure 2: String database interaction network of mir-370-3p and target proteins
Figure 2: Cytoscape constructed networks for pathway analysis of miRNAs target mRNA list

Table-1 Significant pathways enriched in miRNAs target list from KEGG database

Index

Name

P-value

Adjusted p-value

Z-score

Combined score

1

Colorectal cancer_Homo sapiens_hsa05210

0.00004363

0.002610

-1.96

19.65

2

ErbB signaling pathway_Homo sapiens_hsa04012

0.00003766

0.002610

-1.90

19.35

3

Pathways in cancer_Homo sapiens_hsa05200

0.00008735

0.002610

-2.00

18.72

4

MAPK signaling pathway_Homo sapiens_hsa04010

0.00008799

0.002610

-1.87

17.47

5

Bladder cancer_Homo sapiens_hsa05219

0.00006857

0.002610

-1.82

17.42

6

Renal cell carcinoma_Homo sapiens_hsa05211

0.00006887

0.002610

-1.81

17.36

7

Chronic myeloid leukemia_Homo sapiens_hsa05220

0.0001214

0.002701

-1.71

15.40

8

HIF-1 signaling pathway_Homo sapiens_hsa04066

0.0001108

0.002701

-1.68

15.32

9

Proteoglycans in cancer_Homo sapiens_hsa05205

0.001447

0.02575

-1.78

11.64

10

MicroRNAs in cancer_Homo sapiens_hsa05206

0.001268

0.02509

-1.72

11.44

 

Table-2 Significant pathways enriched in miRNAs target list from PANTHER database

Index

Name

P-value

Adjusted p-value

Z-score

Combined score

1

p53 pathway feedback loops 2_Homo sapiens_P04398

0.001279

0.05882

-1.66

11.04

2

EGF receptor signaling pathway_Homo sapiens_P00018

0.006002

0.1034

-1.67

8.54

3

p53 pathway_Homo sapiens_P00059

0.006743

0.1034

-1.33

6.64

4

Interleukin signaling pathway_Homo sapiens_P00036

0.01305

0.1339

-1.32

5.73

5

Angiogenesis_Homo sapiens_P00005

0.01746

0.1339

-1.18

4.79

6

Toll receptor signaling pathway_Homo sapiens_P00054

0.01494

0.1339

-1.04

4.36

7

CCKR signaling map ST_Homo sapiens_P06959

0.03086

0.2028

-1.23

4.29

8

Ras Pathway_Homo sapiens_P04393

0.03649

0.2055

-0.95

3.14

9

T cell activation_Homo sapiens_P00053

0.04202

0.2055

-0.80

2.55

10

Integrin signalling pathway_Homo sapiens_P00034

0.08346

0.2953

-0.63

1.58