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: NCL

Gene summary for NCL

Gene summary.

Gene information	Species	Human
	Gene symbol	NCL
	Gene ID	4691
	Gene name	nucleolin
	Gene Alias	C23
	Cytomap	2q37.1
	Gene Type	protein-coding
	GO ID	GO:0000375
	UniProtAcc	A0A024R4A0

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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
4691	NCL	CA_HPV_1	Human	Cervix	CC	4.72e-16	6.24e-02	0.0264
4691	NCL	CA_HPV_3	Human	Cervix	CC	1.94e-02	2.23e-01	0.0414
4691	NCL	CCI_1	Human	Cervix	CC	1.52e-15	-9.54e-01	0.528
4691	NCL	CCI_3	Human	Cervix	CC	2.24e-02	-4.02e-01	0.516
4691	NCL	CCII_1	Human	Cervix	CC	2.21e-17	-8.02e-01	0.3249
4691	NCL	Tumor	Human	Cervix	CC	1.33e-11	-4.11e-01	0.1241
4691	NCL	sample3	Human	Cervix	CC	5.01e-17	-3.74e-01	0.1387
4691	NCL	L1	Human	Cervix	CC	3.17e-10	-5.94e-01	0.0802
4691	NCL	T1	Human	Cervix	CC	4.68e-03	-3.47e-01	0.0918
4691	NCL	T3	Human	Cervix	CC	1.71e-15	-3.70e-01	0.1389
4691	NCL	HTA11_3410_2000001011	Human	Colorectum	AD	1.81e-06	2.44e-01	0.0155
4691	NCL	HTA11_1938_2000001011	Human	Colorectum	AD	2.19e-09	6.93e-01	-0.0811
4691	NCL	HTA11_78_2000001011	Human	Colorectum	AD	3.71e-09	6.10e-01	-0.1088
4691	NCL	HTA11_347_2000001011	Human	Colorectum	AD	1.01e-22	8.11e-01	-0.1954
4691	NCL	HTA11_83_2000001011	Human	Colorectum	SER	1.63e-05	5.53e-01	-0.1526
4691	NCL	HTA11_696_2000001011	Human	Colorectum	AD	4.22e-09	5.12e-01	-0.1464
4691	NCL	HTA11_866_2000001011	Human	Colorectum	AD	1.96e-07	4.30e-01	-0.1001
4691	NCL	HTA11_1391_2000001011	Human	Colorectum	AD	4.45e-18	1.20e+00	-0.059
4691	NCL	HTA11_546_2000001011	Human	Colorectum	AD	3.76e-06	6.57e-01	-0.0842
4691	NCL	HTA11_7862_2000001011	Human	Colorectum	AD	1.71e-09	7.95e-01	-0.0179

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ
Thyroid		ATC: Anaplastic thyroid cancer
		HT: Hashimoto's thyroiditis
		PTC: Papillary thyroid cancer

∗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:1903313110	Thyroid	PTC	positive regulation of mRNA metabolic process	76/5968	118/18723	3.60e-13	1.80e-11	76
GO:0033120112	Thyroid	PTC	positive regulation of RNA splicing	27/5968	37/18723	3.42e-07	5.75e-06	27
GO:005068516	Thyroid	PTC	positive regulation of mRNA processing	24/5968	32/18723	6.76e-07	1.07e-05	24
GO:0070849111	Thyroid	PTC	response to epidermal growth factor	32/5968	49/18723	1.56e-06	2.19e-05	32
GO:003424916	Thyroid	PTC	negative regulation of cellular amide metabolic process	122/5968	273/18723	5.50e-06	6.64e-05	122
GO:0071364111	Thyroid	PTC	cellular response to epidermal growth factor stimulus	29/5968	45/18723	7.13e-06	8.38e-05	29
GO:001714815	Thyroid	PTC	negative regulation of translation	108/5968	245/18723	3.75e-05	3.48e-04	108
GO:0048026110	Thyroid	PTC	positive regulation of mRNA splicing, via spliceosome	16/5968	22/18723	9.98e-05	8.15e-04	16
GO:00063566	Thyroid	PTC	regulation of transcription by RNA polymerase I	20/5968	34/18723	1.07e-03	6.32e-03	20
GO:00063604	Thyroid	PTC	transcription by RNA polymerase I	28/5968	55/18723	2.55e-03	1.31e-02	28
GO:199082310	Thyroid	PTC	response to leukemia inhibitory factor	42/5968	95/18723	7.69e-03	3.27e-02	42
GO:00987814	Thyroid	PTC	ncRNA transcription	27/5968	56/18723	7.77e-03	3.29e-02	27
GO:199083010	Thyroid	PTC	cellular response to leukemia inhibitory factor	41/5968	94/18723	1.10e-02	4.38e-02	41
GO:00459434	Thyroid	PTC	positive regulation of transcription by RNA polymerase I	13/5968	23/18723	1.25e-02	4.88e-02	13
GO:000838034	Thyroid	ATC	RNA splicing	270/6293	434/18723	7.50e-35	1.19e-31	270
GO:000037534	Thyroid	ATC	RNA splicing, via transesterification reactions	200/6293	324/18723	1.75e-25	7.39e-23	200
GO:000037734	Thyroid	ATC	RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	197/6293	320/18723	6.54e-25	2.18e-22	197
GO:000039834	Thyroid	ATC	mRNA splicing, via spliceosome	197/6293	320/18723	6.54e-25	2.18e-22	197
GO:190331134	Thyroid	ATC	regulation of mRNA metabolic process	181/6293	288/18723	1.75e-24	5.54e-22	181
GO:003164734	Thyroid	ATC	regulation of protein stability	177/6293	298/18723	4.08e-20	6.46e-18	177

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0513020	Cervix	CC	Pathogenic Escherichia coli infection	63/1267	197/8465	9.28e-10	2.00e-08	1.19e-08	63
hsa05130110	Cervix	CC	Pathogenic Escherichia coli infection	63/1267	197/8465	9.28e-10	2.00e-08	1.19e-08	63
hsa05130	Colorectum	AD	Pathogenic Escherichia coli infection	79/2092	197/8465	1.05e-06	1.36e-05	8.65e-06	79
hsa051301	Colorectum	AD	Pathogenic Escherichia coli infection	79/2092	197/8465	1.05e-06	1.36e-05	8.65e-06	79
hsa051302	Colorectum	SER	Pathogenic Escherichia coli infection	60/1580	197/8465	3.63e-05	4.31e-04	3.13e-04	60
hsa051303	Colorectum	SER	Pathogenic Escherichia coli infection	60/1580	197/8465	3.63e-05	4.31e-04	3.13e-04	60
hsa051304	Colorectum	MSS	Pathogenic Escherichia coli infection	73/1875	197/8465	1.10e-06	1.48e-05	9.06e-06	73
hsa051305	Colorectum	MSS	Pathogenic Escherichia coli infection	73/1875	197/8465	1.10e-06	1.48e-05	9.06e-06	73
hsa051306	Colorectum	MSI-H	Pathogenic Escherichia coli infection	31/797	197/8465	2.90e-03	2.93e-02	2.46e-02	31
hsa051307	Colorectum	MSI-H	Pathogenic Escherichia coli infection	31/797	197/8465	2.90e-03	2.93e-02	2.46e-02	31
hsa051308	Colorectum	FAP	Pathogenic Escherichia coli infection	62/1404	197/8465	1.37e-07	3.08e-06	1.87e-06	62
hsa051309	Colorectum	FAP	Pathogenic Escherichia coli infection	62/1404	197/8465	1.37e-07	3.08e-06	1.87e-06	62
hsa0513010	Colorectum	CRC	Pathogenic Escherichia coli infection	47/1091	197/8465	1.49e-05	3.84e-04	2.60e-04	47
hsa0513011	Colorectum	CRC	Pathogenic Escherichia coli infection	47/1091	197/8465	1.49e-05	3.84e-04	2.60e-04	47
hsa0513026	Endometrium	AEH	Pathogenic Escherichia coli infection	50/1197	197/8465	1.72e-05	1.86e-04	1.36e-04	50
hsa05130112	Endometrium	AEH	Pathogenic Escherichia coli infection	50/1197	197/8465	1.72e-05	1.86e-04	1.36e-04	50
hsa0513027	Endometrium	EEC	Pathogenic Escherichia coli infection	51/1237	197/8465	1.98e-05	2.28e-04	1.70e-04	51
hsa0513036	Endometrium	EEC	Pathogenic Escherichia coli infection	51/1237	197/8465	1.98e-05	2.28e-04	1.70e-04	51
hsa05130211	Esophagus	ESCC	Pathogenic Escherichia coli infection	142/4205	197/8465	8.21e-11	1.06e-09	5.42e-10	142
hsa05130310	Esophagus	ESCC	Pathogenic Escherichia coli infection	142/4205	197/8465	8.21e-11	1.06e-09	5.42e-10	142

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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
MDK	NCL	MDK_NCL	MK	Breast	ADJ
MDK	NCL	MDK_NCL	MK	Breast	DCIS
PTN	NCL	PTN_NCL	PTN	Breast	DCIS
MDK	NCL	MDK_NCL	MK	Breast	Healthy
PTN	NCL	PTN_NCL	PTN	Breast	Healthy
MDK	NCL	MDK_NCL	MK	Breast	IDC
MDK	NCL	MDK_NCL	MK	Breast	Precancer
MDK	NCL	MDK_NCL	MK	Cervix	ADJ
PTN	NCL	PTN_NCL	PTN	Cervix	ADJ
MDK	NCL	MDK_NCL	MK	Cervix	CC
PTN	NCL	PTN_NCL	PTN	Cervix	CC
MDK	NCL	MDK_NCL	MK	Cervix	Healthy
MDK	NCL	MDK_NCL	MK	Cervix	Precancer
PTN	NCL	PTN_NCL	PTN	Cervix	Precancer
MDK	NCL	MDK_NCL	MK	CRC	AD
PTN	NCL	PTN_NCL	PTN	CRC	AD
MDK	NCL	MDK_NCL	MK	CRC	ADJ
MDK	NCL	MDK_NCL	MK	CRC	MSI-H
MDK	NCL	MDK_NCL	MK	CRC	MSS
MDK	NCL	MDK_NCL	MK	CRC	SER

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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

NCL

SNV

Missense_Mutation

novel

c.581A>G

p.Asp194Gly

p.D194G

P19338

protein_coding

tolerated_low_confidence(0.07)

benign(0)

TCGA-A8-A083-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NCL

SNV

Missense_Mutation

rs769718813

c.511G>A

p.Glu171Lys

p.E171K

P19338

protein_coding

tolerated_low_confidence(0.21)

benign(0.003)

TCGA-A8-A095-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

NCL

SNV

Missense_Mutation

c.94N>A

p.Glu32Lys

p.E32K

P19338

protein_coding

deleterious_low_confidence(0.01)

benign(0.257)

TCGA-A8-A0A7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

NCL

SNV

Missense_Mutation

c.2063N>A

p.Gly688Glu

p.G688E

P19338

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.999)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NCL

SNV

Missense_Mutation

c.2021N>T

p.Gly674Val

p.G674V

P19338

protein_coding

deleterious_low_confidence(0.02)

probably_damaging(0.989)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NCL

SNV

Missense_Mutation

novel

c.700G>A

p.Glu234Lys

p.E234K

P19338

protein_coding

tolerated(0.37)

benign(0.005)

TCGA-BH-A18U-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

NCL

SNV

Missense_Mutation

c.1789N>T

p.Arg597Trp

p.R597W

P19338

protein_coding

deleterious(0.03)

probably_damaging(0.983)

TCGA-C8-A27A-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

NCL

SNV

Missense_Mutation

c.871N>G

p.Pro291Ala

p.P291A

P19338

protein_coding

tolerated(0.07)

benign(0.1)

TCGA-D8-A1J8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

nolvadex

NCL

SNV

Missense_Mutation

c.368N>C

p.Gly123Ala

p.G123A

P19338

protein_coding

tolerated_low_confidence(0.13)

benign(0.175)

TCGA-D8-A1XQ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NCL

SNV

Missense_Mutation

novel

c.790G>A

p.Glu264Lys

p.E264K

P19338

protein_coding

tolerated(0.05)

benign(0.19)

TCGA-D8-A27G-01

Breast

breast invasive carcinoma

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
4691	NCL	NA		AS1411
4691	NCL	NA		IPP-204106
4691	NCL	NA		Itarnafloxin	QUARFLOXIN	21455236
4691	NCL	NA		IPP-204106
4691	NCL	NA		ACT-GRO-777		25057429

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