TISIDB

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Secreted.
Domain	PF01291 LIF / OSM family
Function	LIF has the capacity to induce terminal differentiation in leukemic cells. Its activities include the induction of hematopoietic differentiation in normal and myeloid leukemia cells, the induction of neuronal cell differentiation, and the stimulation of acute-phase protein synthesis in hepatocytes.

> Gene Ontology [ TOP ]
Biological Process	GO:0001655 urogenital system development GO:0001656 metanephros development GO:0001701 in utero embryonic development GO:0001822 kidney development GO:0001890 placenta development GO:0001892 embryonic placenta development GO:0001893 maternal placenta development GO:0001933 negative regulation of protein phosphorylation GO:0001974 blood vessel remodeling GO:0002521 leukocyte differentiation GO:0002573 myeloid leukocyte differentiation GO:0002761 regulation of myeloid leukocyte differentiation GO:0002763 positive regulation of myeloid leukocyte differentiation GO:0003337 mesenchymal to epithelial transition involved in metanephros morphogenesis GO:0003338 metanephros morphogenesis GO:0003339 regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis GO:0006473 protein acetylation GO:0006475 internal protein amino acid acetylation GO:0007126 meiotic nuclear division GO:0007259 JAK-STAT cascade GO:0007260 tyrosine phosphorylation of STAT protein GO:0007517 muscle organ development GO:0007565 female pregnancy GO:0007566 embryo implantation GO:0009914 hormone transport GO:0010001 glial cell differentiation GO:0010639 negative regulation of organelle organization GO:0010720 positive regulation of cell development GO:0010817 regulation of hormone levels GO:0010948 negative regulation of cell cycle process GO:0014013 regulation of gliogenesis GO:0014015 positive regulation of gliogenesis GO:0016570 histone modification GO:0016573 histone acetylation GO:0018105 peptidyl-serine phosphorylation GO:0018108 peptidyl-tyrosine phosphorylation GO:0018205 peptidyl-lysine modification GO:0018209 peptidyl-serine modification GO:0018212 peptidyl-tyrosine modification GO:0018393 internal peptidyl-lysine acetylation GO:0018394 peptidyl-lysine acetylation GO:0019827 stem cell population maintenance GO:0023061 signal release GO:0030099 myeloid cell differentiation GO:0030225 macrophage differentiation GO:0030323 respiratory tube development GO:0030324 lung development GO:0030856 regulation of epithelial cell differentiation GO:0030858 positive regulation of epithelial cell differentiation GO:0031056 regulation of histone modification GO:0031058 positive regulation of histone modification GO:0033135 regulation of peptidyl-serine phosphorylation GO:0033138 positive regulation of peptidyl-serine phosphorylation GO:0033139 regulation of peptidyl-serine phosphorylation of STAT protein GO:0033141 positive regulation of peptidyl-serine phosphorylation of STAT protein GO:0034504 protein localization to nucleus GO:0035065 regulation of histone acetylation GO:0035066 positive regulation of histone acetylation GO:0035850 epithelial cell differentiation involved in kidney development GO:0040020 regulation of meiotic nuclear division GO:0042063 gliogenesis GO:0042326 negative regulation of phosphorylation GO:0042501 serine phosphorylation of STAT protein GO:0042503 tyrosine phosphorylation of Stat3 protein GO:0042508 tyrosine phosphorylation of Stat1 protein GO:0042509 regulation of tyrosine phosphorylation of STAT protein GO:0042510 regulation of tyrosine phosphorylation of Stat1 protein GO:0042511 positive regulation of tyrosine phosphorylation of Stat1 protein GO:0042516 regulation of tyrosine phosphorylation of Stat3 protein GO:0042517 positive regulation of tyrosine phosphorylation of Stat3 protein GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein GO:0043409 negative regulation of MAPK cascade GO:0043410 positive regulation of MAPK cascade GO:0043543 protein acylation GO:0043966 histone H3 acetylation GO:0043974 histone H3-K27 acetylation GO:0044706 multi-multicellular organism process GO:0045637 regulation of myeloid cell differentiation GO:0045639 positive regulation of myeloid cell differentiation GO:0045649 regulation of macrophage differentiation GO:0045651 positive regulation of macrophage differentiation GO:0045685 regulation of glial cell differentiation GO:0045687 positive regulation of glial cell differentiation GO:0045786 negative regulation of cell cycle GO:0045835 negative regulation of meiotic nuclear division GO:0046425 regulation of JAK-STAT cascade GO:0046427 positive regulation of JAK-STAT cascade GO:0046697 decidualization GO:0046879 hormone secretion GO:0046883 regulation of hormone secretion GO:0046888 negative regulation of hormone secretion GO:0048286 lung alveolus development GO:0048568 embryonic organ development GO:0048608 reproductive structure development GO:0048644 muscle organ morphogenesis GO:0048708 astrocyte differentiation GO:0048710 regulation of astrocyte differentiation GO:0048711 positive regulation of astrocyte differentiation GO:0048771 tissue remodeling GO:0048861 leukemia inhibitory factor signaling pathway GO:0048863 stem cell differentiation GO:0050730 regulation of peptidyl-tyrosine phosphorylation GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation GO:0050769 positive regulation of neurogenesis GO:0051048 negative regulation of secretion GO:0051051 negative regulation of transport GO:0051098 regulation of binding GO:0051101 regulation of DNA binding GO:0051321 meiotic cell cycle GO:0051445 regulation of meiotic cell cycle GO:0051447 negative regulation of meiotic cell cycle GO:0051783 regulation of nuclear division GO:0051784 negative regulation of nuclear division GO:0051962 positive regulation of nervous system development GO:0060135 maternal process involved in female pregnancy GO:0060231 mesenchymal to epithelial transition GO:0060425 lung morphogenesis GO:0060426 lung vasculature development GO:0060462 lung lobe development GO:0060463 lung lobe morphogenesis GO:0060541 respiratory system development GO:0060706 cell differentiation involved in embryonic placenta development GO:0060707 trophoblast giant cell differentiation GO:0060708 spongiotrophoblast differentiation GO:0060712 spongiotrophoblast layer development GO:0060993 kidney morphogenesis GO:0061005 cell differentiation involved in kidney development GO:0061326 renal tubule development GO:0061458 reproductive system development GO:0070371 ERK1 and ERK2 cascade GO:0070372 regulation of ERK1 and ERK2 cascade GO:0070373 negative regulation of ERK1 and ERK2 cascade GO:0072001 renal system development GO:0072006 nephron development GO:0072009 nephron epithelium development GO:0072028 nephron morphogenesis GO:0072073 kidney epithelium development GO:0072077 renal vesicle morphogenesis GO:0072080 nephron tubule development GO:0072087 renal vesicle development GO:0072088 nephron epithelium morphogenesis GO:0072108 positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis GO:0072160 nephron tubule epithelial cell differentiation GO:0072170 metanephric tubule development GO:0072182 regulation of nephron tubule epithelial cell differentiation GO:0072202 cell differentiation involved in metanephros development GO:0072207 metanephric epithelium development GO:0072210 metanephric nephron development GO:0072215 regulation of metanephros development GO:0072216 positive regulation of metanephros development GO:0072234 metanephric nephron tubule development GO:0072243 metanephric nephron epithelium development GO:0072257 metanephric nephron tubule epithelial cell differentiation GO:0072273 metanephric nephron morphogenesis GO:0072283 metanephric renal vesicle morphogenesis GO:0072307 regulation of metanephric nephron tubule epithelial cell differentiation GO:0090183 regulation of kidney development GO:0090184 positive regulation of kidney development GO:0097696 STAT cascade GO:0098727 maintenance of cell number GO:1900180 regulation of protein localization to nucleus GO:1900182 positive regulation of protein localization to nucleus GO:1901674 regulation of histone H3-K27 acetylation GO:1901676 positive regulation of histone H3-K27 acetylation GO:1901983 regulation of protein acetylation GO:1901985 positive regulation of protein acetylation GO:1902105 regulation of leukocyte differentiation GO:1902107 positive regulation of leukocyte differentiation GO:1902275 regulation of chromatin organization GO:1902532 negative regulation of intracellular signal transduction GO:1903025 regulation of RNA polymerase II regulatory region sequence-specific DNA binding GO:1903046 meiotic cell cycle process GO:1903531 negative regulation of secretion by cell GO:1903706 regulation of hemopoiesis GO:1903708 positive regulation of hemopoiesis GO:1903829 positive regulation of cellular protein localization GO:1904892 regulation of STAT cascade GO:1904894 positive regulation of STAT cascade GO:1905269 positive regulation of chromatin organization GO:1905330 regulation of morphogenesis of an epithelium GO:1905332 positive regulation of morphogenesis of an epithelium GO:2000027 regulation of organ morphogenesis GO:2000241 regulation of reproductive process GO:2000242 negative regulation of reproductive process GO:2000677 regulation of transcription regulatory region DNA binding GO:2000696 regulation of epithelial cell differentiation involved in kidney development GO:2000698 positive regulation of epithelial cell differentiation involved in kidney development GO:2000756 regulation of peptidyl-lysine acetylation GO:2000758 positive regulation of peptidyl-lysine acetylation
Molecular Function	GO:0001076 transcription factor activity, RNA polymerase II transcription factor binding GO:0001134 transcription factor activity, transcription factor recruiting GO:0001135 transcription factor activity, RNA polymerase II transcription factor recruiting GO:0005125 cytokine activity GO:0005126 cytokine receptor binding GO:0005146 leukemia inhibitory factor receptor binding GO:0008083 growth factor activity
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04060 Cytokine-cytokine receptor interaction hsa04550 Signaling pathways regulating pluripotency of stem cells hsa04630 Jak-STAT signaling pathway hsa04668 TNF signaling pathway
Reactome	R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-6788467: IL-6-type cytokine receptor ligand interactions R-HSA-168256: Immune System R-HSA-6783783: Interleukin-10 signaling R-HSA-6785807: Interleukin-4 and 13 signaling R-HSA-6783589: Interleukin-6 family signaling R-HSA-449147: Signaling by Interleukins

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between LIF and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

[ TOP ]

Literatures describing the relation between LIF and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
28533357	Prostate Carcinoma	Inhibit immunity	TLR9 expression and secretion of LIF by prostate cancer cells stimulates accumulation and activity of polymorphonuclear MDSCs. The PMN-MDSCs from tetracycline-treated RM9-Tlr9ONtumors increased the immunosuppressive activity of the STAT3 transcription factor, thereby more potently inhibiting T cell proliferation.
17848619	Ovarian Carcinoma	Inhibit immunity (T cell function)	Ovarian cancer ascites contained high concentrations of LIF and IL-6. Recombinant LIF and IL-6 skew monocyte differentiation into TAM-like cells by enabling monocytes to consume monocyte-colony-stimulating factor (M-CSF). Depletion of LIF, IL-6, and M-CSF in ovarian cancer ascites suppressed TAM-like cell induction.

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

[ TOP ]

Statistical results of LIF in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

[ TOP ]

Points in the above scatter plot represent the expression difference of LIF in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-0.921	0.228
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.301	0.859
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-1.365	0.269
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.028	0.97
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.221	0.889
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.352	0.871
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.182	0.831
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.726	0.604
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	1.455	0.273
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.077	0.951
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.153	0.93
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.853	0.000153

> Mutation difference between responders and non-responders

[ TOP ]

Points in the above scatter plot represent the mutation difference of LIF in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	7.4	7.4	0.0709
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	7.4	7.4	0.096
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	2.6	2.6	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	4.5	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	1

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of LIF. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of LIF. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by LIF. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of LIF. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of LIF expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between LIF and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	LIF
Name	leukemia inhibitory factor
Aliases	HILDA; differentiation inhibitory activity; differentiation-inducing factor; hepatocyte-stimulating factor I ......
Chromosomal Location	22q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting LIF collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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