Decreased Expression of PTPN12 Correlates with Tumor Recurrence and Poor Survival of Patients with Hepatocellular Carcinoma

Luo, Rong; Cai, Pei; Li, Mei; Fu, Jia; Zhang, Zhi Yi; Chen, Jie Wei; Cao, Yun; Yun, Jing Ping; Xie, Dan; Cai, Mu Yan

doi:10.1371/journal.pone.0085592

Cited by 36 publications

(40 citation statements)

References 28 publications

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“…In this study, we propose that PTPN12 plays a key role in CD99-mediated negative regulation of ␤1 integrin activity and tumor progression. This assumption is consistent with recent reports showing that PTPN12 functions as a tumor suppressor (67)(68)(69). Taken together, our results suggest that CD99-derived agonist ligands have potential as novel therapeutic reagents to suppress tumor progression via negative regulation of ␤1 integrin activity.…”

Section: Discussionsupporting

confidence: 93%

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

Lee

Kim

Yoo

et al. 2017

Molecular and Cellular Biology

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The human CD99 protein is a 32-kDa glycosylated transmembrane protein that regulates various cellular responses, including cell adhesion and leukocyte extravasation. We previously reported that CD99 activation suppresses ␤1 integrin activity through dephosphorylation of focal adhesion kinase (FAK) at Y397. We explored a molecular mechanism underlying the suppression of ␤1 integrin activity by CD99 agonists and its relevance to tumor growth in vivo. CD99-Fc fusion proteins or a series of CD99-derived peptides suppressed ␤1 integrin activity by specifically interacting with three conserved motifs of the CD99 extracellular domain. CD99CRIII3, a representative CD99-derived 3-mer peptide, facilitated protein kinase A-SHP2 interaction and subsequent activation of the HRAS/RAF1/MEK/ERK signaling pathway. Subsequently, CD99CRIII3 induced FAK phosphorylation at S910, which led to the recruitment of PTPN12 and PIN1 to FAK, followed by FAK dephosphorylation at Y397. Taken together, these results indicate that CD99-derived agonist ligands inhibit fibronectin-mediated ␤1 integrin activation through the SHP2/ERK/PTPN12/FAK signaling pathway.

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Section: Discussionsupporting

confidence: 93%

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

Lee

Kim

Yoo

et al. 2017

Molecular and Cellular Biology

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“…This alteration was more common in TNBC. Likewise, decreased expression of PTPN12 was reported in other human malignancies, including non-small-cell lung carcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma, and hepatocellular carcinoma (18)(19)(20)(21). In all cases, loss of PTPN12 correlated with aggressiveness and poor prognosis.…”

mentioning

confidence: 63%

“…This could also be the case for other types of human cancer in which loss of PTPN12 is more often seen in aggressive subtypes. These include lung cancer, nasopharyngeal cancer, esophageal cancer, and hepatocellular carcinoma (14,18,20,21).…”

Section: Discussionmentioning

confidence: 99%

Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Davidson

Souza

et al. 2015

Molecular and Cellular Biology

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e PTPN12 is a cytoplasmic protein tyrosine phosphatase (PTP) reported to be a tumor suppressor in breast cancer, through its capacity to dephosphorylate oncogenic receptor protein tyrosine kinases (PTKs), such as ErbB2. However, the precise molecular and cellular impact of PTPN12 deficiency in breast cancer progression remains to be fully clarified. Here, we addressed this issue by examining the effect of PTPN12 deficiency on breast cancer progression in vivo, in a mouse model of ErbB2-dependent breast cancer using a conditional PTPN12-deficient mouse. Our studies showed that lack of PTPN12 in breast epithelial cells accelerated breast cancer development and lung metastases in vivo. PTPN12-deficient breast cancer cells displayed enhanced tyrosine phosphorylation of the adaptor Cas, the adaptor paxillin, and the kinase Pyk2. They exhibited no detectable increase in ErbB2 tyrosine phosphorylation. PTPN12-deficient cells were more resistant to anoikis and had augmented migratory and invasive properties. Enhanced migration was corrected by inhibiting Pyk2. PTPN12-deficient breast cancer cells also acquired partial features of epithelial-to-mesenchymal transition (EMT), a feature of more aggressive forms of breast cancer. Hence, loss of PTPN12 promoted tumor progression in a mouse model of breast cancer, supporting the notion that PTPN12 is a tumor suppressor in human breast cancer. This function was related to the ability of PTPN12 to suppress cell survival, migration, invasiveness, and EMT and to inhibit tyrosine phosphorylation of Cas, Pyk2, and paxillin. These findings enhance our understanding of the role and mechanism of action of PTPN12 in the control of breast cancer progression. P rotein tyrosine phosphatases (PTPs) play a key role in normal cellular processes, such as proliferation, migration, adhesion, differentiation, and immune cell activation (1-3). Depending on the phosphatase and the cell type, they also have the ability either to suppress or to promote malignant transformation (3). PTPN12, also referred to as PTP-PEST (PTP-proline, glutamic acid, serine, and threonine rich), is a cytoplasmic PTP expressed in a wide spectrum of cell types (4). Studies of PTPN12-deficient mice showed that PTPN12 is a critical positive regulator of migration and adhesion in embryonic fibroblasts, endothelial cells, T cells, macrophages, and dendritic cells (5-11). This function relates to the capacity of PTPN12 to dephosphorylate cytoskeletonassociated substrates such as protein tyrosine kinases (PTKs) Pyk2 and FAK or the adaptors Cas, paxillin, and PSTPIP-1. These substrates are components of the cellular machinery controlling migration and adhesion. PTPN12 can also regulate other substrates, including receptor PTKs, such as ErbB2 and the adaptor . Proteomic data suggested that the ability of PTPN12 to regulate Shc might be critical for conversion of Shc-dependent proliferative signals into migratory signals (15). Several PTPN12 substrates, and in particular, Cas, paxillin, and Shc, also directly associate with PTPN12....

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“…We also showed that knockdown of PTPN12 significantly increased the migration capacity and expression of mesenchymal markers and EMT-TFs in multiple human HCC cell lines, indicating that PTPN12 is a universal EMT suppressor in cancer cells as well as in normal tissues. Decreased expression of PTPN12 is also negatively correlated with tumor recurrence and survival of HCC patients (56), further supporting the importance of this tumor suppressor in HCC. Interestingly, Ptpn12-deficient mouse embryos exhibited a failure of liver development, leading to lethality (57), suggesting that Ptpn12 may play a fundamental role in liver development as well.…”

Section: Discussionmentioning

confidence: 83%

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

Kodama

Newberg

Kodama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMTTFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, nonreceptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets.H CC is the sixth most common cancer and the third-leading cause of cancer-related deaths worldwide (1). In the United States, the incidence of HCC is increasing, and overall 5-y survival is now <12%, despite recent progress in diagnostic and therapeutic modalities (2). This high mortality rate is related mainly to a high recurrence rate and associated intrahepatic or extrahepatic metastases (1). Patients with HCC who develop metastasis are no longer eligible for liver transplantation therapy and have very limited therapeutic options. Currently, sorafenib is the sole systemic antineoplastic agent for HCC described in the National Comprehensive Cancer Network (NCCN) guideline (3); however, its clinical benefit is limited (4), and alternative effective treatments are needed for these patients.Epithelial-mesenchymal transition (EMT) is a complex differentiation process whereby epithelial cells lose their identity and acquire mesenchymal characteristics (5). EMT is observed routinely in developmental processes, but is also believed to play an important role in the migration, invasion, and metastasis of various cancers (6-9). It also promotes the generation of cancer stem cells, thereby contributing to tumor recurrence and metastasis...

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Decreased Expression of PTPN12 Correlates with Tumor Recurrence and Poor Survival of Patients with Hepatocellular Carcinoma

Cited by 36 publications

References 28 publications

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

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