Protein tyrosine phosphatase nonreceptor 2: A New biomarker for digestive tract cancers

Table 1 Recent findings of the clinicopathological studies in gastrointestinal cancers related to protein tyrosine phosphatase nonreceptor 2

Ref.	Organ	Expression	Clinicopathologic parameters	Methods	Prognosis	Therapy related findings
Chen et al[29]	Esophagus	High	NS	Oncomine, Ualcan, TCGA data analysis	NS	-
Tang et al[1]	Esophagus	High	-	TCGA, GTEx, CGGA, GEO, cBioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	Positive correlation with TMB and higher TIDE scores; Poor response to therapy
Chen et al[29]	Stomach	High	NS	Oncomine,Ualcan, TCGA data analysis	NS	-
Tang et al[1]	Stomach	High	-	TCGA, GTEx, CGGA, GEO,c BioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	Positive correlation with TMB, MSI, tumor purity, polyploidy and HRD
Chen et al[29]	Colon	High	NS	Oncomine, Ualcan, TCGA data	NS	-
Tang et al[1]	Colon	High	-	TCGA, GTEx, CGGA, GEO, cBioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	Positive correlation with high immune scores; Positive correlation with neoantigems; Negative correlation with tumor purity, polyploidy and HRD
Zhang et al[18]	Pancreas	Down regulated	-	Human tumor tissue, IHC, RT-PCR, IF, WB, CC, AE	Poor prognosis	-
Kuang et al[25]	Pancreas	High	Positive correlation with stage	Human tumor tissue, IHC, RT-PCR, IF, WB, CC, AE	Poor prognosis; Independent prognostic	Positive correlation with high immune scores
Tang et al[1]	Pancreas	High	-	TCGA, GTEx, CGGA, GEO, cBioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	Poor prognosis	Positive correlation with high immune scores; Positive correlation with HRD, TMB, MSI, tumor purity, polyploidy and HRD
Lee et al[27]	Liver (HCC)	Down regulated	Positive correlation with stage	Human tumor tissue	Poor prognosis	-
Tang et al[1]	Liver (HCC)	High	-	TCGA, GTEx, CGGA, GEO, c BioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	Positive correlation with high immune scores; Negative correlation with TMB and tumor purity; Positive correlation with HRD and TIDE scores; Poor response to therapy
Tang et al[1]	Liver (CHOL)	High	-	TCGA, GTEx, CGGA, GEO,c BioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, TIDE data analysis	NS	NS
Li et al[10]	Liver (HCC)	High	Positive correlation with preoperative alfa-protein	TCGA data analysis	Poor prognosis Independent prognostic	Higher immune cell infiltration, EMT and angiogenesis; Positive correlation with TGF-β, Notch and Hedgehog signaling pathways upregulation

Ualcan: The University of Alabama at Birmingham Cancer data analysis Portal; TCGA: The Cancer Genome Atlas; GTEX: Genotype tissue expression project; CGGA: Chinese Glioma Genome Atlas; GEO: Gene expression Omnibus database; STRING: Functional protein association networks; TISCH: Tumor Immune Single-cell Hub; TIMER 2.0: Web server for analysis of tumor-infiltrating immune cells; -: Not performed; TMB: Tumor mutation burden; TIDE: Tumor immune disfunction and exclusion; IHC: Immunohistochemistry; RT-PCR; Reverse transcriptase polymerase chain reaction; IF: Immunofluorescence ; WB: Western blotting; CC: Cell culture; AE: Animal experiment; MSI: Microsatellite instability; HRD: Homologous recombination deficiencies; HCC: Hepatocellular carcinoma; CHOL: Cholangiocarcinoma; EMT: Epithelial-to-mesenchymal transition; NS: Not significant.

Table 2 Recent findings of the experimental studies in gastrointestinal cancers related to protein tyrosine phosphatase nonreceptor 2

Ref.	Organ	Methods	Findings related to PPTN2
Spalinger et al[14]	Colon	CC, IF	PPTN2 dysfunction in T cells drives the secretion of IFN-γ and IL-17. PPTN2 dysfunction promotes IL-18, IL-1β secretion and increased inflammasome assembly. Protects from CRC development
Manguso et al[15]	Colon	AE	Loss of PTPN2 enhances Tim-3+ CD8+ T cell differentiation promoting anti-tumor immunity
Tang et al[1]	Colon	TCGA, GTEx data analysis	Positive correlation with CD8+ cells. Knockdown inhibits proliferation of cancer cells and leads to abundance of PD-L1
Huang et al[26]	Pancreas	CC, WB	Silencing PTPN2 attenuates the proliferation of cancer cells. PTPN2 regulates the level of tyrosine phosphorylation of KRAS. PTPN2 knockdown was consistent with that of knockdown of KRAS
Kuang et al[25]	Pancreas	TCGA, GTEx data analysis	PTPN2 mRNA expression upregulated and related to JAK-STAT pathway. Down-regulation diminishes tumor burden
Zhang et al[18]	Pancreas	Human tumor tissue, IHC, RT-PCR, IF, WB, CC, AE	Knockdown promotes the migration and invasion abilities. PTPN2 inhibited metastasis, and presented a novel PTPN2/p-STAT3/MMP-1 axis in progression
Grohmann et al[28]	HCC	AE	PTPN2 deletion in hepatocytes promoted T cell recruitment. PTPN2 deletion promotes STAT-3 dependent HCC
Tang et al[1]	HCC	TCGA, GTEx data analysis	Terminal differentiation-induced lncRNA preserved STAT3 phosphorylation via direct interacting with PTPN2. The activation of STAT3 downstream target genes and promote HCC cell growth, migration, and infiltration

CC: Cell culture; IF: Immunofluorescence; CRC: Colorectal cancer; AE: Animal experiment; TCGA: The Cancer Genome Atlas; GTEX: Genotype tissue expression project; IHC: Immunohistochemistry; RT-PCR: Reverse transcriptase polymerase chain reaction; IF: Immunofluorescence; WB: Western blotting; MMP-1: Matrix metalloproteinase-1; lncRNA: Long non-coding RNA; HCC: Hepatocellular carcinoma; PTPN2: Protein tyrosine phosphatase nonreceptor 2.