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: SLC9A3

Gene summary for SLC9A3

Gene summary.

Gene information	Species	Human
	Gene symbol	SLC9A3
	Gene ID	6550
	Gene name	solute carrier family 9 member A3
	Gene Alias	DIAR8
	Cytomap	5p15.33
	Gene Type	protein-coding
	GO ID	GO:0006810
	UniProtAcc	P48764

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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
6550	SLC9A3	S014	Human	Liver	HCC	4.34e-20	4.44e-01	0.2254
6550	SLC9A3	S015	Human	Liver	HCC	6.67e-18	5.50e-01	0.2375
6550	SLC9A3	S016	Human	Liver	HCC	3.89e-23	5.22e-01	0.2243
6550	SLC9A3	S027	Human	Liver	HCC	3.40e-03	2.35e-01	0.2446
6550	SLC9A3	S028	Human	Liver	HCC	4.40e-18	5.47e-01	0.2503
6550	SLC9A3	S029	Human	Liver	HCC	1.31e-14	3.82e-01	0.2581

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Liver		HCC: Hepatocellular carcinoma
Liver		NAFLD: Non-alcoholic fatty liver disease

∗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:199077814	Endometrium	EEC	protein localization to cell periphery	69/2168	333/18723	9.71e-07	3.31e-05	69
GO:009719327	Esophagus	HGIN	intrinsic apoptotic signaling pathway	90/2587	288/18723	1.50e-14	2.80e-12	90
GO:200124227	Esophagus	HGIN	regulation of intrinsic apoptotic signaling pathway	58/2587	164/18723	2.57e-12	3.58e-10	58
GO:200123327	Esophagus	HGIN	regulation of apoptotic signaling pathway	97/2587	356/18723	1.36e-11	1.57e-09	97
GO:200124410	Esophagus	HGIN	positive regulation of intrinsic apoptotic signaling pathway	25/2587	58/18723	4.91e-08	2.75e-06	25
GO:200123519	Esophagus	HGIN	positive regulation of apoptotic signaling pathway	41/2587	126/18723	6.06e-08	3.22e-06	41
GO:005165616	Esophagus	HGIN	establishment of organelle localization	90/2587	390/18723	4.27e-07	1.94e-05	90
GO:000734610	Esophagus	HGIN	regulation of mitotic cell cycle	98/2587	457/18723	4.39e-06	1.42e-04	98
GO:190260017	Esophagus	HGIN	proton transmembrane transport	43/2587	157/18723	5.51e-06	1.75e-04	43
GO:007265920	Esophagus	HGIN	protein localization to plasma membrane	66/2587	284/18723	1.11e-05	3.18e-04	66
GO:199077818	Esophagus	HGIN	protein localization to cell periphery	71/2587	333/18723	1.05e-04	2.24e-03	71
GO:004873225	Esophagus	HGIN	gland development	88/2587	436/18723	1.34e-04	2.71e-03	88
GO:00101557	Esophagus	HGIN	regulation of proton transport	10/2587	24/18723	7.66e-04	1.00e-02	10
GO:00516455	Esophagus	HGIN	Golgi localization	7/2587	14/18723	1.34e-03	1.57e-02	7
GO:003011116	Esophagus	HGIN	regulation of Wnt signaling pathway	65/2587	328/18723	1.53e-03	1.77e-02	65
GO:00459305	Esophagus	HGIN	negative regulation of mitotic cell cycle	49/2587	235/18723	1.88e-03	2.01e-02	49
GO:001605516	Esophagus	HGIN	Wnt signaling pathway	83/2587	444/18723	2.27e-03	2.33e-02	83
GO:019873816	Esophagus	HGIN	cell-cell signaling by wnt	83/2587	446/18723	2.58e-03	2.55e-02	83
GO:004340919	Esophagus	HGIN	negative regulation of MAPK cascade	38/2587	180/18723	4.58e-03	3.96e-02	38
GO:006082816	Esophagus	HGIN	regulation of canonical Wnt signaling pathway	50/2587	253/18723	5.27e-03	4.35e-02	50

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

SLC9A3

SNV

Missense_Mutation

c.2153N>T

p.Ser718Leu

p.S718L

P48764

protein_coding

tolerated(0.06)

benign(0)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SLC9A3

SNV

Missense_Mutation

c.838A>C

p.Lys280Gln

p.K280Q

P48764

protein_coding

deleterious(0.01)

probably_damaging(0.984)

TCGA-AR-A0TS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

SLC9A3

SNV

Missense_Mutation

c.917N>G

p.Leu306Arg

p.L306R

P48764

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-C8-A134-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

SLC9A3

SNV

Missense_Mutation

c.688G>A

p.Val230Met

p.V230M

P48764

protein_coding

tolerated(0.25)

possibly_damaging(0.82)

TCGA-E9-A244-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

SLC9A3

deletion

Frame_Shift_Del

novel

c.978delN

p.Asn326LysfsTer14

p.N326Kfs*14

P48764

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

SLC9A3

SNV

Missense_Mutation

novel

c.1250C>T

p.Ala417Val

p.A417V

P48764

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SLC9A3

SNV

Missense_Mutation

rs755154955

c.2048N>A

p.Arg683Gln

p.R683Q

P48764

protein_coding

deleterious(0.03)

benign(0.129)

TCGA-EK-A2PM-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

SLC9A3

SNV

Missense_Mutation

novel

c.782N>A

p.Gly261Asp

p.G261D

P48764

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-VS-A9UJ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

SLC9A3

insertion

Frame_Shift_Ins

novel

c.2031_2032insA

p.Ala678SerfsTer50

p.A678Sfs*50

P48764

protein_coding

TCGA-DG-A2KH-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

SLC9A3

SNV

Missense_Mutation

c.287N>A

p.Gly96Asp

p.G96D

P48764

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A6-2686-01

Colorectum

colon adenocarcinoma

Female

>=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
6550	SLC9A3	DRUGGABLE GENOME, TRANSPORTER, CELL SURFACE, EXCHANGER		GLUCOCORTICOID		9727362
6550	SLC9A3	DRUGGABLE GENOME, TRANSPORTER, CELL SURFACE, EXCHANGER		AZD1722
6550	SLC9A3	DRUGGABLE GENOME, TRANSPORTER, CELL SURFACE, EXCHANGER	inhibitor	CHEMBL2107782
6550	SLC9A3	DRUGGABLE GENOME, TRANSPORTER, CELL SURFACE, EXCHANGER		AVE-0657
6550	SLC9A3	DRUGGABLE GENOME, TRANSPORTER, CELL SURFACE, EXCHANGER		AZD1772//RDX5791
6550	SLC9A3	DRUGGABLE GENOME, TRANSPORTER, CELL SURFACE, EXCHANGER	inhibitor	CHEMBL3301627	TENAPANOR HYDROCHLORIDE
6550	SLC9A3	DRUGGABLE GENOME, TRANSPORTER, CELL SURFACE, EXCHANGER		RDX-5791	TENAPANOR HYDROCHLORIDE
6550	SLC9A3	DRUGGABLE GENOME, TRANSPORTER, CELL SURFACE, EXCHANGER		ALBUMIN	ALBUMIN HUMAN	11251045,11698229

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