Schematic overview of the cellular and molecular mechanisms involved in the cancer progression, including the proposed cellular and molecular mechanisms in cancer cells trajectory. AT1: alveolar type 1 cells; AT2: alveolar type 2 cells; AAH: atypical adenomatous hyperplasia; AIS: adenocarcinoma in situ; MIA: minimally invasive adenocarcinoma; IA: invasive adenocarcinoma; EMT: epithelial-mesenchymal transition

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	Gene summary
	Malignant transformation analysis
	Malignant transformation related pathway analysis
	Cell-cell communication analysis
	Single-cell gene regulatory network inference analysis
	Somatic mutation of malignant transformation related genes
	Related drugs of malignant transformation related genes

Gene: MAP2K3

Gene summary for MAP2K3

Gene summary.

Gene information	Species	Human
	Gene symbol	MAP2K3
	Gene ID	5606
	Gene name	mitogen-activated protein kinase kinase 3
	Gene Alias	MAPKK3
	Cytomap	17p11.2
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	P46734

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Malignant transformation analysis

Identification of the aberrant gene expression in precancerous and cancerous lesions by comparing the gene expression of stem-like cells in diseased tissues with normal stem cells

Malignant transformation involving gene list.

Entrez ID	Symbol	Replicates	Species	Organ	Tissue	Adj P-value	Log2FC	Malignancy
5606	MAP2K3	HTA11_2487_2000001011	Human	Colorectum	SER	2.70e-09	7.55e-01	-0.1808
5606	MAP2K3	HTA11_1938_2000001011	Human	Colorectum	AD	3.80e-02	3.62e-01	-0.0811
5606	MAP2K3	HTA11_347_2000001011	Human	Colorectum	AD	5.06e-04	2.61e-01	-0.1954
5606	MAP2K3	HTA11_696_2000001011	Human	Colorectum	AD	3.00e-05	2.98e-01	-0.1464
5606	MAP2K3	HTA11_866_2000001011	Human	Colorectum	AD	4.27e-02	1.91e-01	-0.1001
5606	MAP2K3	HTA11_1391_2000001011	Human	Colorectum	AD	1.80e-04	4.60e-01	-0.059
5606	MAP2K3	HTA11_7696_3000711011	Human	Colorectum	AD	2.98e-09	3.66e-01	0.0674
5606	MAP2K3	HTA11_99999970781_79442	Human	Colorectum	MSS	9.71e-09	3.55e-01	0.294
5606	MAP2K3	HTA11_99999971662_82457	Human	Colorectum	MSS	5.51e-05	2.70e-01	0.3859
5606	MAP2K3	HTA11_99999974143_84620	Human	Colorectum	MSS	1.18e-06	3.30e-01	0.3005
5606	MAP2K3	LZE4T	Human	Esophagus	ESCC	5.09e-19	-1.83e-01	0.0811
5606	MAP2K3	LZE7T	Human	Esophagus	ESCC	9.66e-05	-2.55e-01	0.0667
5606	MAP2K3	LZE8T	Human	Esophagus	ESCC	2.36e-08	-2.06e-01	0.067
5606	MAP2K3	LZE20T	Human	Esophagus	ESCC	4.55e-10	-3.22e-01	0.0662
5606	MAP2K3	LZE24T	Human	Esophagus	ESCC	1.25e-05	4.59e-01	0.0596
5606	MAP2K3	LZE21T	Human	Esophagus	ESCC	1.59e-02	8.47e-02	0.0655
5606	MAP2K3	LZE6T	Human	Esophagus	ESCC	1.73e-05	-4.00e-01	0.0845
5606	MAP2K3	P2T-E	Human	Esophagus	ESCC	1.42e-14	4.44e-01	0.1177
5606	MAP2K3	P4T-E	Human	Esophagus	ESCC	7.82e-16	4.54e-01	0.1323
5606	MAP2K3	P5T-E	Human	Esophagus	ESCC	3.08e-06	-1.40e-01	0.1327

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Colorectum (GSE201348)		FAP: Familial adenomatous polyposis
		CRC: Colorectal cancer
Colorectum (HTA11)		AD: Adenomas
		SER: Sessile serrated lesions
		MSI-H: Microsatellite-high colorectal cancer
		MSS: Microsatellite stable colorectal cancer
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
Prostate		BPH: Benign Prostatic Hyperplasia

∗log2FC in expression of this searched gene in stem-like cells from each diseased tissue sample relative to stem-like cells in normal samples in each tissue plotted against the malignancy continuum. Samples are colored based on if they are from different disease stage.

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Malignant transformation related pathway analysis

Find out the enriched GO biological processes and KEGG pathways involved in transition from healthy to precancer to cancer

Figure of enriched GO biological processes.

Tissue	Disease Stage	Enriched GO biological Processes
Colorectum	AD
Colorectum	SER
Colorectum	MSS
Colorectum	MSI-H
Colorectum	FAP

∗Top 15 enriched GO BP terms are showed in the bar plot of each disease state in each tissue. Each row represents a significant GO biological process which is colored according to the -log10(p.adjust).

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Enriched GO biological processes.

GO ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	Count
GO:0001667	Colorectum	AD	ameboidal-type cell migration	137/3918	475/18723	2.17e-05	4.33e-04	137
GO:0090132	Colorectum	AD	epithelium migration	105/3918	360/18723	1.18e-04	1.73e-03	105
GO:0010632	Colorectum	AD	regulation of epithelial cell migration	88/3918	292/18723	1.19e-04	1.75e-03	88
GO:0033674	Colorectum	AD	positive regulation of kinase activity	131/3918	467/18723	1.28e-04	1.85e-03	131
GO:0010631	Colorectum	AD	epithelial cell migration	104/3918	357/18723	1.33e-04	1.90e-03	104
GO:0090130	Colorectum	AD	tissue migration	105/3918	365/18723	2.10e-04	2.77e-03	105
GO:0007568	Colorectum	AD	aging	98/3918	339/18723	2.77e-04	3.39e-03	98
GO:0010634	Colorectum	AD	positive regulation of epithelial cell migration	56/3918	176/18723	4.51e-04	5.03e-03	56
GO:0051403	Colorectum	AD	stress-activated MAPK cascade	72/3918	239/18723	4.77e-04	5.25e-03	72
GO:0031098	Colorectum	AD	stress-activated protein kinase signaling cascade	74/3918	247/18723	4.80e-04	5.27e-03	74
GO:0045860	Colorectum	AD	positive regulation of protein kinase activity	107/3918	386/18723	8.01e-04	7.92e-03	107
GO:0043542	Colorectum	AD	endothelial cell migration	78/3918	279/18723	2.97e-03	2.22e-02	78
GO:0010595	Colorectum	AD	positive regulation of endothelial cell migration	40/3918	133/18723	8.01e-03	4.73e-02	40
GO:00016671	Colorectum	SER	ameboidal-type cell migration	105/2897	475/18723	6.97e-05	1.59e-03	105
GO:00901321	Colorectum	SER	epithelium migration	82/2897	360/18723	1.50e-04	2.93e-03	82
GO:00106311	Colorectum	SER	epithelial cell migration	81/2897	357/18723	1.87e-04	3.44e-03	81
GO:00901301	Colorectum	SER	tissue migration	82/2897	365/18723	2.40e-04	4.12e-03	82
GO:00106321	Colorectum	SER	regulation of epithelial cell migration	68/2897	292/18723	2.72e-04	4.53e-03	68
GO:00336741	Colorectum	SER	positive regulation of kinase activity	95/2897	467/18723	2.62e-03	2.41e-02	95
GO:00435421	Colorectum	SER	endothelial cell migration	61/2897	279/18723	2.76e-03	2.47e-02	61

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa049351	Colorectum	MSS	Growth hormone synthesis, secretion and action	42/1875	120/8465	8.17e-04	5.16e-03	3.16e-03	42
hsa040155	Colorectum	MSS	Rap1 signaling pathway	66/1875	210/8465	1.03e-03	5.94e-03	3.64e-03	66
hsa051691	Colorectum	MSS	Epstein-Barr virus infection	63/1875	202/8465	1.63e-03	8.98e-03	5.50e-03	63
hsa051611	Colorectum	MSS	Hepatitis B	48/1875	162/8465	1.53e-02	4.93e-02	3.02e-02	48
hsa05014210	Esophagus	ESCC	Amyotrophic lateral sclerosis	266/4205	364/8465	1.31e-20	2.20e-18	1.13e-18	266
hsa05132211	Esophagus	ESCC	Salmonella infection	191/4205	249/8465	6.51e-19	5.45e-17	2.79e-17	191
hsa05022210	Esophagus	ESCC	Pathways of neurodegeneration - multiple diseases	318/4205	476/8465	6.10e-15	2.04e-13	1.05e-13	318
hsa05169210	Esophagus	ESCC	Epstein-Barr virus infection	151/4205	202/8465	1.55e-13	3.45e-12	1.77e-12	151
hsa0421829	Esophagus	ESCC	Cellular senescence	119/4205	156/8465	5.89e-12	9.40e-11	4.81e-11	119
hsa04714211	Esophagus	ESCC	Thermogenesis	163/4205	232/8465	9.22e-11	1.14e-09	5.86e-10	163
hsa0466810	Esophagus	ESCC	TNF signaling pathway	89/4205	114/8465	3.36e-10	4.01e-09	2.06e-09	89
hsa05170210	Esophagus	ESCC	Human immunodeficiency virus 1 infection	147/4205	212/8465	3.37e-09	3.53e-08	1.81e-08	147
hsa0513526	Esophagus	ESCC	Yersinia infection	100/4205	137/8465	1.80e-08	1.59e-07	8.12e-08	100
hsa05417211	Esophagus	ESCC	Lipid and atherosclerosis	143/4205	215/8465	3.30e-07	2.45e-06	1.26e-06	143
hsa051619	Esophagus	ESCC	Hepatitis B	108/4205	162/8465	7.68e-06	4.15e-05	2.12e-05	108
hsa0514525	Esophagus	ESCC	Toxoplasmosis	76/4205	112/8465	6.83e-05	2.90e-04	1.48e-04	76
hsa052356	Esophagus	ESCC	PD-L1 expression and PD-1 checkpoint pathway in cancer	58/4205	89/8465	2.19e-03	6.16e-03	3.16e-03	58
hsa0501438	Esophagus	ESCC	Amyotrophic lateral sclerosis	266/4205	364/8465	1.31e-20	2.20e-18	1.13e-18	266
hsa05132310	Esophagus	ESCC	Salmonella infection	191/4205	249/8465	6.51e-19	5.45e-17	2.79e-17	191
hsa0502238	Esophagus	ESCC	Pathways of neurodegeneration - multiple diseases	318/4205	476/8465	6.10e-15	2.04e-13	1.05e-13	318

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Cell-cell communication analysis

Identification of potential cell-cell interactions between two cell types and their ligand-receptor pairs for different disease states

Ligand

Receptor

LRpair

Pathway

Tissue

Disease Stage

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Single-cell gene regulatory network inference analysis

Find out the significant the regulons (TFs) and the target genes of each regulon across cell types for different disease states

Cell Type

Tissue

Disease Stage

Target Gene

RSS

Regulon Activity

∗The dot plots of a searched regulon are shown for all cell subpopulations in each disease state of each tissue based on the regulon specific score inferred using pySCENIC and by calculating the average expression.

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Somatic mutation of malignant transformation related genes

Annotation of somatic variants for genes involved in malignant transformation

Hugo Symbol

Variant Class

Variant Classification

dbSNP RS

HGVSc

HGVSp

HGVSp Short

SWISSPROT

BIOTYPE

SIFT

PolyPhen

Tumor Sample Barcode

Tissue

Histology

Sex

Age

Stage

Therapy Types

Drugs

Outcome

MAP2K3

SNV

Missense_Mutation

rs748513234

c.466G>T

p.Asp156Tyr

p.D156Y

P46734

protein_coding

deleterious(0)

possibly_damaging(0.526)

TCGA-AN-A0FX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

MAP2K3

SNV

Missense_Mutation

novel

c.545N>A

p.Ser182Asn

p.S182N

P46734

protein_coding

tolerated(0.1)

benign(0.034)

TCGA-D8-A1XR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin+cyclophosphamide

MAP2K3

SNV

Missense_Mutation

rs148304866

c.455N>A

p.Arg152Gln

p.R152Q

P46734

protein_coding

deleterious(0.02)

benign(0.003)

TCGA-JL-A3YW-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

MAP2K3

insertion

Frame_Shift_Ins

novel

c.900_901insATAAAGGAGTACGAGGTTGAAGG

p.Phe301IlefsTer14

p.F301Ifs*14

P46734

protein_coding

TCGA-AO-A0J9-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

MAP2K3

SNV

Missense_Mutation

c.778N>C

p.Glu260Gln

p.E260Q

P46734

protein_coding

deleterious(0)

probably_damaging(0.959)

TCGA-C5-A3HE-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

MAP2K3

SNV

Missense_Mutation

c.50N>C

p.Gly17Ala

p.G17A

P46734

protein_coding

tolerated(0.54)

benign(0.033)

TCGA-FU-A2QG-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

MAP2K3

SNV

Missense_Mutation

novel

c.140G>T

p.Arg47Leu

p.R47L

P46734

protein_coding

tolerated(0.07)

benign(0.137)

TCGA-VS-A8EL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

MAP2K3

SNV

Missense_Mutation

c.1028T>C

p.Leu343Pro

p.L343P

P46734

protein_coding

deleterious(0)

probably_damaging(0.959)

TCGA-AA-3710-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

MAP2K3

SNV

Missense_Mutation

rs775653621

c.119N>A

p.Pro40His

p.P40H

P46734

protein_coding

deleterious(0)

possibly_damaging(0.819)

TCGA-AA-3950-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

MAP2K3

SNV

Missense_Mutation

c.931N>T

p.Ala311Ser

p.A311S

P46734

protein_coding

tolerated(0.74)

benign(0.009)

TCGA-AA-3977-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

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Related drugs of malignant transformation related genes

Identification of chemicals and drugs interact with genes involved in malignant transfromation

(DGIdb 4.0)

Entrez ID	Symbol	Category	Interaction Types	Drug Claim Name	Drug Name	PMIDs
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE	inhibitor	TRAMETINIB	TRAMETINIB
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE	inhibitor	AZD6244	SELUMETINIB
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE	inhibitor	DABRAFENIB MESYLATE
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE		WX-554	WX-554
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE	inhibitor	MEK162	BINIMETINIB
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE		ROSIGLITAZONE	ROSIGLITAZONE	11591391
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE	inhibitor	BAY869766
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE	inhibitor	GDC-0973	COBIMETINIB
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE	inhibitor	178102628
5606	MAP2K3	KINASE, DRUGGABLE GENOME, TRANSPORTER, ENZYME, SERINE THREONINE KINASE, TYROSINE KINASE	inhibitor	SELUMETINIB	SELUMETINIB

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