PTPN13 rs989902 and CHEK2 rs738722 are associated with esophageal cancer.

PURPOSE: Individual genetic background can play an essential role in determining the development of esophageal squamous cell carcinoma (ESCC). PTPN13 and CHEK2 play important roles in the pathogenesis of ESCC. This case-control study aimed to analyze the association between gene polymorphisms and ESCC susceptibility. METHODS: DNA was extracted from the peripheral blood of patients. The Agena MassARRAY platform was used for the genotyping. Statistical analysis was conducted using the chi-squared test or Fisher's exact test, logistic regression analysis, and stratification analysis. RESULTS: The 'G' allele of rs989902 (PTPN13) and the 'T' allele of rs738722 (CHEK2) were both associated with an increased risk of ESCC (rs989902: OR = 1.23, 95% CI = 1.02-1.47, p = 0.028; rs738722: OR = 1.28, 95% CI = 1.06-1.55, p = 0.011). Stratification analysis showed that SNPs (rs989902 and rs738722) were notably correlated with an increased risk of ESCC after stratification for age, sex, smoking, and drinking status. In addition, rs738722 might be associated with lower stage, while rs989902 had a lower risk of metastasis. CONCLUSION: Our findings display that PTPN13 rs989902 and CHEK2 rs738722 are associated with an increased risk of ESCC in the Chinese Han population.

PTPN13 Participates in the Regulation of Epithelial-Mesenchymal Transition and Platinum Sensitivity in High-Grade Serous Ovarian Carcinoma Cells.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological cancers in Western countries. High-Grade Serous Ovarian Carcinoma (HGSOC) accounts for 60-70% of EOC and is the most aggressive subtype. Reduced PTPN13 expression levels have been previously correlated with worse prognosis in HGSOC. However, PTPN13's exact role and mechanism of action in these tumors remained to be investigated. To elucidate PTPN13's role in HGSOC aggressiveness, we used isogenic PTPN13-overexpressing clones of the OVCAR-8 cell line, which poorly expresses PTPN13, and also PTPN13 CRISPR/Cas9-mediated knockout/knockdown clones of the KURAMOCHI cell line, which strongly expresses PTPN13. We investigated their migratory and invasive capacity using a wound healing assay, their mesenchymal-epithelial transition (EMT) status using microscopy and RT-qPCR, and their sensitivity to chemotherapeutic drugs used for HGSOC. We found that (i) PTPN13 knockout/knockdown increased migration and invasion in KURAMOCHI cells that also displayed a more mesenchymal phenotype and increased expression of the SLUG, SNAIL, ZEB-1, and ZEB-2 EMT master genes; and (ii) PTPN13 expression increased the platinum sensitivity of HGSOC cells. These results suggest that PTPN13 might be a predictive marker of response to platinum salts in HGSOC.

Comprehensive analysis of the PTPN13 expression and its clinical implication in breast cancer.

Protein tyrosine phosphatases non-receptor 13 (PTPN13) could be a potential biomarker in breast cancer (BRCA), but its genetic variation and biological significance in BRCA remain undefined. Hereon, we comprehensively investigated the clinical implication of PTPN13 expression/gene mutation in BRCA. In our study, a total of 14 cases of triple-negative breast cancers (TNBC) treated with neoadjuvant therapy were enrolled, and post-operation TNBC tissues were collected for next-generation sequencing (NGS) analysis (422 genes including PTPN13). According to the disease-free survival (DFS) time, 14 TNBC patients were divided into Group A (long-DFS) and Group B (short-DFS). The NGS data displayed that the overall mutation rate of PTPN13 was 28.57% as the third highest mutated gene, and PTPN13 mutations appeared only in Group B with short-DFS. In addition, The Cancer Genome Atlas (TCGA) database demonstrated that PTPN13 was lower expressed in BRCA than in normal breast tissues. However, PTPN13 high expression was identified to be related to a favorable prognosis in BRCA using data from the Kaplan-Meier plotter. Moreover, Gene Set Enrichment Analysis (GSEA) revealed that PTPN13 is potentially involved in interferon signaling, JAK/STAT signaling, Wnt/ß-catenin signaling, PTEN pathway, and MAPK6/MAPK4 signaling in BRCA. This study provided evidence that PTPN13 might be a tumor suppressor gene and a potential molecular target for BRCA, and genetic mutation and/or low expression of PTPN13 predicted an unfavorable prognosis in BRCA. The anticancer effect and molecular mechanism of PTPN13 in BRCA may be associated with some tumor-related signaling pathways.

Atomic resolution protein allostery from the multi-state structure of a PDZ domain.

Recent methodological advances in solution NMR allow the determination of multi-state protein structures and provide insights into structurally and dynamically correlated protein sites at atomic resolution. This is demonstrated in the present work for the well-studied PDZ2 domain of protein human tyrosine phosphatase 1E for which protein allostery had been predicted. Two-state protein structures were calculated for both the free form and in complex with the RA-GEF2 peptide using the exact nuclear Overhauser effect (eNOE) method. In the apo protein, an allosteric conformational selection step comprising almost 60% of the domain was detected with an "open" ligand welcoming state and a "closed" state that obstructs the binding site by changing the distance between the ß-sheet 2, α-helix 2, and sidechains of residues Lys38 and Lys72. The observed induced fit-type apo-holo structural rearrangements are in line with the previously published evolution-based analysis covering ~25% of the domain with only a partial overlap with the protein allostery of the open form. These presented structural studies highlight the presence of a dedicated highly optimized and complex dynamic interplay of the PDZ2 domain owed by the structure-dynamics landscape.

Exome sequencing of early-onset patients supports genetic heterogeneity in colorectal cancer.

Colorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight.

Host PDZ-containing proteins targeted by SARS-CoV-2.

Small linear motifs targeting protein interacting domains called PSD-95/Dlg/ZO-1 (PDZ) have been identified at the C terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins E, 3a, and N. Using a high-throughput approach of affinity-profiling against the full human PDZome, we identified sixteen human PDZ binders of SARS-CoV-2 proteins E, 3A, and N showing significant interactions with dissociation constants values ranging from 3 to 82 µm. Six of them (TJP1, PTPN13, HTRA1, PARD3, MLLT4, LNX2) are also recognized by SARS-CoV while three (NHERF1, MAST2, RADIL) are specific to SARS-CoV-2 E protein. Most of these SARS-CoV-2 protein partners are involved in cellular junctions/polarity and could be also linked to evasion mechanisms of the immune responses during viral infection. Among the binders of the SARS-CoV-2 proteins E, 3a, or N, seven significantly affect viral replication under knock down gene expression in infected cells. This PDZ profiling identifying human proteins potentially targeted by SARS-CoV-2 can help to understand the multifactorial severity of COVID19 and to conceive effective anti-coronaviral agents for therapeutic purposes.

Co-delivery of siPTPN13 and siNOX4 via (myo)fibroblast-targeting polymeric micelles for idiopathic pulmonary fibrosis therapy.

Rationale: (Myo)fibroblasts are the ultimate effector cells responsible for the production of collagen within alveolar structures, a core phenomenon in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Although (myo)fibroblast-targeted therapy holds great promise for suppressing the progression of IPF, its development is hindered by the limited drug delivery efficacy to (myo)fibroblasts and the vicious circle of (myo)fibroblast activation and evasion of apoptosis. Methods: Here, a dual small interfering RNA (siRNA)-loaded delivery system of polymeric micelles is developed to suppress the development of pulmonary fibrosis via a two-arm mechanism. The micelles are endowed with (myo)fibroblast-targeting ability by modifying the Fab' fragment of the anti-platelet-derived growth factor receptor-α (PDGFRα) antibody onto their surface. Two different sequences of siRNA targeting protein tyrosine phosphatase-N13 (PTPN13, a promoter of the resistance of (myo)fibroblasts to Fas-induced apoptosis) and NADPH oxidase-4 (NOX4, a key regulator for (myo)fibroblast differentiation and activation) are loaded into micelles to inhibit the formation of fibroblastic foci. Results: We demonstrate that Fab'-conjugated dual siRNA-micelles exhibit higher affinity to (myo)fibroblasts in fibrotic lung tissue. This Fab'-conjugated dual siRNA-micelle can achieve remarkable antifibrotic effects on the formation of fibroblastic foci by, on the one hand, suppressing (myo)fibroblast activation via siRNA-induced knockdown of NOX4 and, on the other hand, sensitizing (myo)fibroblasts to Fas-induced apoptosis by siRNA-mediated PTPN13 silencing. In addition, this (myo)fibroblast-targeting siRNA-loaded micelle did not induce significant damage to major organs, and no histopathological abnormities were observed in murine models. Conclusion: The (myo)fibroblast-targeting dual siRNA-loaded micelles offer a potential strategy with promising prospects in molecular-targeted fibrosis therapy.

Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression.

Hepatitis B x protein (HBx) affects cellular protein expression and participates in the tumorigenesis and progression of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Metabolic reprogramming contributed to the HCC development, but its role in HBV-related HCC remains largely unclear. Tyrosine-protein phosphatase nonreceptor type 13 (PTPN13) is a significant regulator in tumor development, however, its specific role in hepatocarcinogenesis remains to be explored. Here, we found that decreased PTPN13 expression was associated with HBV/HBx. Patients with low PTPN13 expression showed a poor prognosis. Functional assays revealed that PTPN13 inhibited proliferation and tumorigenesis in vitro and in vivo. Further mechanistic studies indicated that HBx inhibited PTPN13 expression by upregulating the expression of DNMT3A and interacting with DNMT3A. Furthermore, we found that DNMT3A bound to the PTPN13 promoter (-343 to -313 bp) in an epigenetically controlled manner associated with elevated DNA methylation and then inhibited PTPN13 transcription. In addition, we identified IGF2BP1 as a novel PTPN13-interacting gene and demonstrated that PTPN13 influences c-Myc expression by directly and competitively binding to IGF2BP1 to decrease the intracellular concentration of functional IGF2BP1. Overexpressing PTPN13 promoted c-Myc mRNA degradation independent of the protein tyrosine phosphatase (PTP) activity of PTPN13. Importantly, we discovered that the PTPN13-IGF2BP1-c-Myc axis was important for cancer cell growth through promoting metabolic reprogramming. We verified the significant negative correlations between PTPN13 expression and c-Myc, PSPH, and SLC7A1 expression in clinical HCC tissue samples. In summary, our findings demonstrate that PTPN13 is a novel regulator of HBV-related hepatocarcinogenesis and may play an important role in HCC. PTPN13 may serve as a prognostic marker and therapeutic target in HBV-related HCC patients.

PTPN13 acts as a tumor suppressor in clear cell renal cell carcinoma by inactivating Akt signaling.

Protein tyrosine phosphatase, nonreceptor type 13 (PTPN13), has emerged as a critical cancer-related gene that is implicated in a wide range of cancer types. However, the role of PTPN13 in clear cell renal cell carcinoma (ccRCC) is poorly understood. In the present study, we aimed to evaluate whether PTPN13 participates in the progression of ccRCC. Decreased expression of PTPN13 was found in ccRCC tissues, which predicted a shorter survival rate in ccRCC patients. PTPN13 expression was also lower in ccRCC cell lines, and the upregulation of PTPN13 repressed the proliferation, colony formation and invasion, but enhanced the apoptosis of ccRCC cells. In contrast, the silencing of PTPN13 produced the opposite effects. Further data showed that PTPN13 overexpression decreased the phosphorylation of Akt, while PTPN13 silencing increased the phosphorylation of Akt. Treatment with Akt inhibitor markedly abrogated the PTPN13 silencing-evoked oncogenic effect in ccRCC cells. Xenograft tumor experiments revealed that overexpression of PTPN13 remarkably restricted the tumor formation and growth of ccRCC cells in vivo associated with inactivation of Akt. In conclusion, our data demonstrated that overexpression of PTPN13 restricts the proliferation and invasion of ccRCC cells through inactivation of Akt. Our study suggests a tumor suppressive function of PTPN13 in ccRCC and highlights the potential role of PTPN13 in the progression of ccRCC.

Protein tyrosine phosphatase L1 represses endothelial-mesenchymal transition by inhibiting IL-1ß/NF-κB/Snail signaling.

Endothelial-mesenchymal transition (EnMT) plays a pivotal role in various diseases, including pulmonary hypertension (PH), and transcription factors like Snail are key regulators of EnMT. In this study we investigated how these factors were regulated by PH risk factors (e.g. inflammation and hypoxia) in human umbilical vein endothelial cells (HUVECs). We showed that treatment with interleukin 1ß (IL-1ß) induced EnMT of HUVECs via activation of NF-κB/Snail pathway, which was further exacerbated by knockdown of protein tyrosine phosphatase L1 (PTPL1). We demonstrated that PTPL1 inhibited NF-κB/Snail through dephosphorylating and stabilizing IκBα. IL-1ß or hypoxia could downregulate PTPL1 expression in HUVECs. The deregulation of PTPL1/NF-κB signaling was validated in a monocrotaline-induced rat PH (MCT-PH) model and clinical PH specimens. Our findings provide novel insights into the regulatory mechanisms of EnMT, and have implications for identifying new therapeutic targets for clinical PH.

Whole Exome Sequencing of Highly Aggregated Lung Cancer Families Reveals Linked Loci for Increased Cancer Risk on Chromosomes 12q, 7p, and 4q.

BACKGROUND: Lung cancer kills more people than any other cancer in the United States. In addition to environmental factors, lung cancer has genetic risk factors as well, though the genetic etiology is still not well understood. We have performed whole exome sequencing on 262 individuals from 28 extended families with a family history of lung cancer. METHODS: Parametric genetic linkage analysis was performed on these samples using two distinct analyses-the lung cancer only (LCO) analysis, where only patients with lung cancer were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected. RESULTS: The AAC analysis yielded a genome-wide significant result at rs61943670 in POLR3B at 12q23.3. POLR3B has been implicated somatically in lung cancer, but this germline finding is novel and is a significant expression quantitative trait locus in lung tissue. Interesting genome-wide suggestive haplotypes were also found within individual families, particularly near SSPO at 7p36.1 in one family and a large linked haplotype spanning 4q21.3-28.3 in a different family. The 4q haplotype contains potential causal rare variants in DSPP at 4q22.1 and PTPN13 at 4q21.3. CONCLUSIONS: Regions on 12q, 7p, and 4q are linked to increased cancer risk in highly aggregated lung cancer families, 12q across families and 7p and 4q within a single family. POLR3B, SSPO, DSPP, and PTPN13 are currently the best candidate genes. IMPACT: Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.

Subtypes of Barrett's oesophagus and oesophageal adenocarcinoma based on genome-wide methylation analysis.

OBJECTIVE: To identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett's oesophagus (BE). DESIGN: We performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies. RESULTS: We identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student's t-test) and the highest global mutation load (p<0.05, Fisher's exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch's t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment. CONCLUSIONS: We identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.

Protein Tyrosine Phosphatase-N13 Promotes Myofibroblast Resistance to Apoptosis in Idiopathic Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic interstitial lung disease characterized by (myo)fibroblast accumulation and collagen deposition. Resistance to Fas-induced apoptosis is thought to facilitate (myo)fibroblast persistence in fibrotic lung tissues by poorly understood mechanisms. OBJECTIVES: To test the hypothesis that PTPN13 (protein tyrosine phosphatase-N13) is expressed by IPF lung (myo)fibroblasts, promotes their resistance to Fas-induced apoptosis, and contributes to the development of pulmonary fibrosis. METHODS: PTPN13 was localized in lung tissues from patients with IPF and control subjects by immunohistochemical staining. Inhibition of PTPN13 function in primary IPF and normal lung (myo)fibroblasts was accomplished by: 1) downregulation with TNF-α (tumor necrosis factor-α)/IFN-γ, 2) siRNA knockdown, or 3) a cell-permeable Fas/PTPN13 interaction inhibitory peptide. The role of PTPN13 in the development of pulmonary fibrosis was assessed in mice with genetic deficiency of PTP-BL, the murine ortholog of PTPN13. MEASUREMENTS AND MAIN RESULTS: PTPN13 was constitutively expressed by (myo)fibroblasts in the fibroblastic foci of patients with IPF. Human lung (myo)fibroblasts, which are resistant to Fas-induced apoptosis, basally expressed PTPN13 in vitro. TNF-α/IFN-γ or siRNA-mediated PTPN13 downregulation and peptide-mediated inhibition of the Fas/PTPN13 interaction in human lung (myo)fibroblasts promoted Fas-induced apoptosis. Bleomycin-challenged PTP-BL-/- mice, while developing inflammatory lung injury, exhibited reduced pulmonary fibrosis compared with wild-type mice. CONCLUSIONS: These findings suggest that PTPN13 mediates the resistance of human lung (myo)fibroblasts to Fas-induced apoptosis and promotes pulmonary fibrosis in mice. Our results suggest that strategies aimed at interfering with PTPN13 expression or function may represent a novel strategy to reduce fibrosis in IPF.

The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing.

Mesenchymal stem cells (MSCs) are capable of secreting exosomes, extracellular vesicles, and cytokines to regulate cell and tissue homeostasis. However, it is unknown whether MSCs use a specific exocytotic fusion mechanism to secrete exosomes and cytokines. We show that Fas binds with Fas-associated phosphatase-1 (Fap-1) and caveolin-1 (Cav-1) to activate a common soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE)-mediated membrane fusion mechanism to release small extracellular vesicles (sEVs) in MSCs. Moreover, we reveal that MSCs produce and secrete interleukin-1 receptor antagonist (IL-1RA) associated with sEVs to maintain rapid wound healing in the gingiva via the Fas/Fap-1/Cav-1 cascade. Tumor necrosis factor-α (TNF-α) serves as an activator to up-regulate Fas and Fap-1 expression via the nuclear factor κB pathway to promote IL-1RA release. This study identifies a previously unknown Fas/Fap-1/Cav-1 axis that regulates SNARE-mediated sEV and IL-1RA secretion in stem cells, which contributes to accelerated wound healing.

The Phosphatase PTPL1 Is Required for PTEN-Mediated Regulation of Apical Membrane Size.

PTEN is a tumor suppressor that is frequently lost in epithelial malignancies. A part of the tumor-suppressive properties of PTEN is attributed to its function in cell polarization and consequently its role in maintaining epithelial tissue integrity. However, surprisingly little is known about the function and regulation of PTEN during epithelial cell polarization. We used clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated gene disruption to delete PTEN in intestinal epithelial Ls174T:W4 cells, which upon differentiation form a microvillus-covered apical membrane (brush border) on a part of the cell cortex, independent of cell-cell junctions. We show that loss of PTEN results in the formation of a larger brush border that, in a fraction of the cells, even spans the entire plasma membrane, revealing that PTEN functions in the regulation of apical membrane size. Depletion of the phosphatase PTPL1 resulted in a similar defect. PTPL1 interacts with PTEN, and this interaction is necessary for apical membrane enrichment of PTEN. Importantly, phosphatase activity of PTPL1 is not required, indicating that PTPL1 functions as an anchor protein in this process. Our work thus demonstrates a novel function for PTEN during cell polarization in controlling apical membrane size and identifies PTPL1 as a critical apical membrane anchor for PTEN in this process.

The tyrosine phosphatase PTPN13/FAP-1 links calpain-2, TBI and tau tyrosine phosphorylation.

Traumatic brain injury (TBI) increases the risk of Alzheimer's disease (AD). Calpain activation and tau hyperphosphorylation have been implicated in both TBI and AD. However, the link between calpain and tau phosphorylation has not been fully identified. We recently discovered that the two major calpain isoforms in the brain, calpain-1 and calpain-2, play opposite functions in synaptic plasticity and neuronal survival/death, which may be related to their different C-terminal PDZ binding motifs. Here, we identify the tyrosine phosphatase PTPN13 as a key PDZ binding partner of calpain-2. PTPN13 is cleaved by calpain-2, which inactivates its phosphatase activity and generates stable breakdown products (P13BPs). We also found that PTPN13 dephosphorylates and inhibits c-Abl. Following TBI, calpain-2 activation cleaved PTPN13, activated c-Abl and triggered tau tyrosine phosphorylation. The activation of this pathway was responsible for the accumulation of tau oligomers after TBI, as post-TBI injection of a calpain-2 selective inhibitor inhibited c-Abl activation and tau oligomer accumulation. Thus, the calpain-2-PTPN13-c-Abl pathway provides a direct link between calpain-2 activation and abnormal tau aggregation, which may promote tangle formation and accelerate the development of AD pathology after repeated concussions or TBI. This study suggests that P13BPs could be potential biomarkers to diagnose mTBI or AD.

Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice. Pkd1 and Smyd2 double-knockout mice lived longer than Pkd1-knockout mice. Targeting SMYD2 with its specific inhibitor, AZ505, delayed cyst growth in both early- and later-stage Pkd1 conditional knockout mouse models. SMYD2 carried out its function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased cystic renal epithelial cell proliferation and survival. We further identified two positive feedback loops that integrate epigenetic regulation and renal inflammation in cyst development: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. These pathways provide mechanisms by which SMYD2 might be induced by cyst fluid IL-6 and TNF-α in ADPKD kidneys. The SMYD2 transcriptional target gene Ptpn13 also linked SMYD2 to other PKD-associated signaling pathways, including ERK, mTOR, and Akt signaling, via PTPN13-mediated phosphorylation.

MicroRNA-30e-5p promotes cell growth by targeting PTPN13 and indicates poor survival and recurrence in lung adenocarcinoma.

Aberrant microRNA expression is involved in the regulation of various cellular processes, such as proliferation and metastasis in multiple diseases including cancers. MicroRNA-30e-5p (miR-30e) was previously reported as an oncogenic or tumour suppressing miRNA in some malignancies, but its function in lung adenocarcinoma (LAC) remains largely undefined. In this study, we found that the expression of miR-30e was increased in LAC tissues and cell lines, associated with tumour size and represented an independent prognostic factor for overall survival and recurrence of LAC patients. Further functional experiments showed that knockdown of miR-30e suppressed cell growth while its overexpression promoted growth of LAC cells and xenografts in vitro and in vivo. Mechanistically, PTPN13 was identified as the direct target of miR-30e in LAC, in which PTPN13 expression was down-regulated in LAC tissues and showed the inverse correlation with miR-30e expression. Overexpression of PTPN13 inhibited cell growth and rescued the proliferation-promoting effect of miR-30e through inhibition of the EGFR signalling. Altogether, our findings suggest that miR-30e could function as an oncogene in LAC via targeting PTPN13 and act as a potential therapeutic target for treating LAC.

The PTPN13 Y2081D (T>G) (rs989902) polymorphism is associated with an increased risk of sporadic colorectal cancer.

AIM: Colorectal cancer (CRC) is one of the most common cancers worldwide and, although the majority of cases are sporadic, its development and progression depends on a range of factors: environmental, genetic and epigenetic. A variety of genetic pathways have been described as being crucial in CRC, including protein tyrosine phosphatases (PTPs). PTPN13 (also called FAP-1) is a non-receptor PTP and interacts with a number of important components of growth and apoptosis pathways. It is also involved in the inhibition of Fas-induced apoptosis. METHOD: The single nucleotide polymorphism genotype at Y2081D (T>G) (rs989902) of PTPN13 exon 39 was determined in DNA extracted from blood samples from 174 sporadic CRC patients and 176 healthy individuals. Also, a meta-analysis was performed based on three articles accessed via the PubMed and ResearchGate databases. RESULTS: The risk of CRC was 2.087 times greater for patients with the GG genotype than for those with the TT genotype (P = 0.0475). In the meta-analysis, a significantly increased risk of cancer associated with the G allele was observed in the squamous cell carcinoma of the head and neck subgroup (TT vs GG+GT, OR 1.23, 95% CI [1.02, 1.47], P = 0.0258), and a significantly decreased risk in the breast cancer subgroup (TT vs GG+GT, OR 0.63, 95% CI [0.41, 0.96], P = 0.0334) and in the CRC subgroup (GT+TT vs GG, OR 0.51, 95% CI [0.41, 0.95], P = 0.0333). CONCLUSION: PTPN13 rs989902 is significantly associated with the risk of CRC in the Polish population. Given that this report provides the first evidence of an association of PTPN13 rs989902 with the risk of CRC in a Caucasian population, further large scale studies are necessary to confirm this finding.

miR-26a desensitizes non-small cell lung cancer cells to tyrosine kinase inhibitors by targeting PTPN13.

Epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have emerged as first-line drugs for non-small cell lung cancers (NSCLCs). However, the resistance to TKIs represents the key limitation for their therapeutic efficacy. We found that miR-26a was upregulated in gefitinib-refractory NSCLCs; miR-26a is downstream of EGFR signaling and directly targets and silences protein tyrosine phosphatase non-receptor type 13 (PTPN13) to maintain the activation of Src, a dephosphorylation substrate of PTPN13, thus reinforcing EGFR pathway in a regulatory circuit. miR-26a inhibition significantly improved NSCLC responses to gefitinib. These data revealed a novel mechanism of NSCLC resistance to TKI treatment.