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:00073463	Liver	Cirrhotic	regulation of mitotic cell cycle	154/4634	457/18723	8.73e-06	1.29e-04	154
GO:001605511	Liver	Cirrhotic	Wnt signaling pathway	150/4634	444/18723	9.75e-06	1.42e-04	150
GO:019873811	Liver	Cirrhotic	cell-cell signaling by wnt	150/4634	446/18723	1.28e-05	1.80e-04	150
GO:000716312	Liver	Cirrhotic	establishment or maintenance of cell polarity	82/4634	218/18723	1.55e-05	2.11e-04	82
GO:003011111	Liver	Cirrhotic	regulation of Wnt signaling pathway	112/4634	328/18723	7.57e-05	8.40e-04	112
GO:000206412	Liver	Cirrhotic	epithelial cell development	80/4634	220/18723	7.63e-05	8.44e-04	80
GO:005165611	Liver	Cirrhotic	establishment of organelle localization	128/4634	390/18723	1.78e-04	1.67e-03	128
GO:006082811	Liver	Cirrhotic	regulation of canonical Wnt signaling pathway	86/4634	253/18723	5.70e-04	4.46e-03	86
GO:006007011	Liver	Cirrhotic	canonical Wnt signaling pathway	97/4634	303/18723	2.42e-03	1.46e-02	97
GO:00226125	Liver	Cirrhotic	gland morphogenesis	43/4634	118/18723	3.03e-03	1.72e-02	43
GO:00510514	Liver	Cirrhotic	negative regulation of transport	141/4634	470/18723	5.06e-03	2.62e-02	141
GO:00516452	Liver	Cirrhotic	Golgi localization	8/4634	14/18723	9.65e-03	4.35e-02	8
GO:00901625	Liver	Cirrhotic	establishment of epithelial cell polarity	14/4634	31/18723	1.05e-02	4.65e-02	14
GO:003001012	Liver	Cirrhotic	establishment of cell polarity	48/4634	143/18723	1.09e-02	4.79e-02	48
GO:200123322	Liver	HCC	regulation of apoptotic signaling pathway	226/7958	356/18723	7.26e-16	5.68e-14	226
GO:009719322	Liver	HCC	intrinsic apoptotic signaling pathway	184/7958	288/18723	1.50e-13	8.32e-12	184
GO:007265921	Liver	HCC	protein localization to plasma membrane	177/7958	284/18723	1.02e-11	4.18e-10	177
GO:002260422	Liver	HCC	regulation of cell morphogenesis	188/7958	309/18723	4.84e-11	1.82e-09	188
GO:199077821	Liver	HCC	protein localization to cell periphery	200/7958	333/18723	6.07e-11	2.23e-09	200
GO:005165621	Liver	HCC	establishment of organelle localization	226/7958	390/18723	4.15e-10	1.34e-08	226

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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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