Berkeley Pharma Tech Journal of Medicine Correspondence: hasset1@gmail.com Keywords: PTPN Digestive cancer Phosphatase Lung cancer Tumor promoter Submitted: May 10, 2023 Accepted: June 30, 2023 Published: December 30, 2023 Full Open Access Creative Commons Attribution License 4.0 Abstract Protein phosphorylation and dephosphorylation are pivotal in regulating protein activity. Two key players, protein tyrosine kinases and protein tyrosine phosphatases (PTPN), especially non-receptor PTPNs, exert opposing influences in this process. While all PTPNs dephosphorylate substrates, their impact on different cancers varies. Some act as tumor suppressors in specific cancers, while in others, they may function as tumor promoters. This review focuses on comprehending the roles of PTPNs in lung and digestive cancers. Notably, lung cancer ranks as the third most common cancer in the US, with around 200,000 new cases reported annually. Despite declining rates in the United States, stomach cancer remains a major cause of cancer-related deaths worldwide. The objective of this review article is to elucidate the functions of PTPN1, PTPN2, PTPN3, PTPN6, PTPN11, PTPN12, and PTPN13 in lung and/or digestive cancers. Emphasis is placed on exploring their potential as prognostic markers or therapeutic targets. Exploring the Therapeutic Potential of PTPN Families in Lung and Digestive Cancers By: Hasset Yishak, Kareem Halwah, and Jiyun Rhim Berkeley Pharma Tech Journal of Medicine | 83 1. Introduction Cancer is a leading cause of death all over the world, and the complications associated with the disease makes it difficult to efficiently treat. Various types of cancer exist, such as lung cancer, gastric cancer, breast cancer, lymphoma, prostate cancer, and kidney cancer. Lung cancer is the second most common cancer in the United States,1 with approximately 80% of lung cancers being non- small lung cancer (NSCLC). Furthermore, lung cancer accounts for the greatest number of deaths stemming from cancer in men with a 5-year survival rate ranging from 10 % to 20%.2 Digestive cancer encompasses different types of cancer, such as gastric and colorectal cancer. Gastric cancer, also known as stomach cancer, significantly affects 1 in 96 men and 1 in 152 women.1 Known as the fifth most common cancer in the world, gastric cancer’s 5-year survival rate is 32%.3 Current cancer treatments include surgery, chemotherapy, hormone therapy, radiation therapy, hyperthermia, immunotherapy, and targeted therapy.4,5 Despite the variety of treatments, these treatments are not fully effective as millions of people continuously die from cancer annually. Thus, there is a strong drive to develop alternative treatments by exploring the molecular mechanisms of various proteins involved in the progression or inhibition of cancer. 1.1 Introduction to PTPN With current experimentation being conducted in regards to novel therapeutics in lung and digestive cancer, this review paper explores, as well as summarizes, the existing body of scientific literature on the family of protein phosphatases known as non-receptor protein tyrosine phosphatases (PTPN). Phosphorylation and dephosphorylation are highly used mechanisms by the cell to regulate signaling within and between cells. Importantly, PTPNs affect tumor progression by dephosphorylating proteins in order to activate or inhibit potentially oncogenic pathways.6 This creates a strong potential for PTPN families to be used as a prognosis marker and/or therapeutic target in treating lung and digestive tract cancers. Therefore, this literature review characterizes the importance of several PTPNs, PTPN 1, 3, 6, 11, 12, 13, by summarizing their roles as a tumor promoter, tumor suppressor or both as well as exploring their molecular mechanisms in digestive and/or lung cancer [Figure 1]. Berkeley Pharma Tech Journal of Medicine | 84 Figure 1: An overview of the role of each PTPN in lung or digestive cancer. PTPNs marked in green have tumor suppressing capabilities, red as tumor promoting, and orange as having both tumor suppressing and promoting capabilities. 2. PTPN1 PTP1B, also known as protein tyrosine phosphatase non-receptor 1B, is encoded by the PTPN1 gene. Its uncontrolled growth is shown to be correlated with growth of digestive cancer, demonstrating PTPN1B’s potential oncogenic role in digestive cancer.7 For CRC (colorectal cancer), PTP1B was associated with CRC patients’ low overall survival; additional studies also support the relationship of PTP1B overexpression and late stage tumors.8 Therefore, PTP1B expression level can be utilized as a possible biomarker for prognosis of late stage tumors, including CRC.9 2.1 Gastric Cancer Likewise, according to the RT-PCR assay, PTP1B was found to be overexpressed in gastric cancer tissues relative to normal gastric cells. Amplification of PTP1B was associated with poor survival of gastric cancer patients.9 Therefore, the amplification of PTP1B can be both used as a biomarker for gastric cancer and indicative for poor survival rate, revealing PTP1B’s oncogenic role as a tumor promoter in gastric carcinogenesis.10 Furthermore, inhibition of PTP1B in gastric cells was associated with hindrance of gastric cancer cell growth in both vitro and vivo. Furthermore, its inhibition changed genome-wide expression of genes related to cell growth; thus, PTP1B can be directly used as cancer therapy to slow down digestive cancer growth.11 Despite there being evidence of PTP1B functioning as a tumor promoter, contrasting ideas in the literature suggest it can also function as a tumor suppressor depending on the cellular context.12 For example, when EGF (Epidermal Growth Factor) binds to its receptor EGFR, it activates the Shc-Grb2-SOS interaction. At the end of interaction, Ras activates MEK/Erk pathway’s Raf and ends with Erk Berkeley Pharma Tech Journal of Medicine | 85 entering the nucleus to activate FGF2 (Fibroblast Growth Factor 2) which causes uncontrolled growth of the cancer.13 If PTP1B does not interfere in the process, FGF2 promotes cancer growth. However, PTP1B can inhibit the process by interacting at the beginning or end of the Shc pathway and/or prohibiting the entry of Erk into the nucleus PTP1B’s inhibition of signaling pathways leads to decrease in cancer growth13 [Figure 2]. Figure 2: Effect of PTP1B on the pathway of cancer growth. When PTP1B prohibits Shc-Grb2-SOS interaction, the growth of cancer is prohibited due to a decreased expression of FGF2. Oppositely, when PTP1B does not stop the pathway, the cancer cells will be able to proliferate and duplicate itself. 2.2 Non-Small Cell Lung Cancer (NSCLC) In regards to NSCLC, PTP1B levels increase with the progression of the cancer, highlighting how increased PTP1B levels are associated with poor survival of patients with NSCLC.14 Additionally, when PTP1B expression was downregulated, Berkeley Pharma Tech Journal of Medicine | 86 there was a decrease in cell proliferation and metastasis in vitro. Likewise, downregulation of PTP1B in mice transfected with NSCLC cells showed a significant decrease in tumor size compared to control mice that had unaltered PTP1B levels. These results provide evidence for PTP1B’s role as a tumor promoter in lung cancer. Mechanistically, PTP1B activates the oncogene, Src (Proto- Oncogene c-Src), which promotes NSCLC proliferation and metastasis. Therefore, designing an inhibitor of PTP1B could be promising in treating NSCLC due to its suggested tumor suppressing capabilities.14 In Lung Adenocarcinoma (LUAD), PTPN1 is downregulated according to comprehensive bioinformatics analysis. Its upregulation has been conferred with overall higher survival rates in patients, demonstrating the overexpression of PTPN1 as a potential therapeutic target for treating LUAD patients. As well, decreased expression can be a prognostic biomarker for lung cancer progression.15 3. PTPN2 In CRC tumor cells, PTPN2 levels are enhanced, with greater PTPN2 gene expression correlated with reduced T cell activity, recruitment, and cytotoxicity.16 It is also inversely correlated with low immune checkpoint molecule expression.16 PTPN2 negatively regulates IFN-γ signaling, a pathway involved in the upregulation of immunity related genes, by dephosphorylating proteins involved in the signaling pathway. Mouse models with tumors deficient in PTPN2 had increased activation of the IFN-γ receptors by the cytokine, IFN- γ, which resulted in the phosphorylation of the signal transducer and transcription protein, STAT1 [Figure 3]. STAT1 is able to homodimerize and enter the nucleus to drive transcription of genes involved in immunity related processes such as MHC-1, possibly PD-1, and others [16-8]. This results in the activation of CD4+ Th1 cells and increases the cytotoxicity of CD8+ T cells, which inhibits the growth of the tumor.16 CD4+ Th1 cells is a type of T helper cell that releases cytokines in response to inflammation and is also involved in the activation and growth of CD8+ T cells, otherwise known as killer T-cells. Therefore, tumors deficient in PTPN2 have increased IFN-γ signaling, which results in a significant reduction of tumor size as well as greater mRNA expression of chemokines, like cxcl9/10/11 and ccl5.16 This suggests that the inhibition of PTPN2 through a small molecule might prove to be an effective potential therapeutic drug. While additional experimentation would need to be conducted to better understand the kinetics involved with the inhibitors, a recent paper by Zhu et al.19 has identified various small noncytotoxic molecule inhibitors that were able to inhibit PTPN2. This resulted in successful upregulation Berkeley Pharma Tech Journal of Medicine | 87 of genes involved in IFN-γ signaling, and the sensitization of the CRC tumor to treatment. 3.1 KRAS Gene Approximately 40% of patients with CRC have a missense mutation in the KRAS (Kirsten rat sarcoma viral oncogene homologue) gene.20 Those with the mutation in the KRAS gene tend to have a relatively poorer prognosis compared to CRC patients with wild type KRAS.20 KRAS encodes for the protein K-ras, which is part of the signaling pathway of RAS/MAPK, a pathway that induces cellular proliferation, migration, and cell growth. Mutations in KRAS are thought to be the most common oncogenic gene driver in human cancer, especially in pancreatic cancer, CRC, and NSCLC.21 These mutations lead to a continued active state of KRAS that result in continuous proliferation of tumor cells by upregulating the RAS/MAPK pathway. PTPN2 has been identified as a key regulator of KRAS due to its ability to dephosphorylate KRAS, activating the KRAS-mediated MAPK pathway.22 Therefore, it is hypothesized that inhibition of PTPN2 could suppress cancer by no longer activating KRAS, presenting itself to be a novel therapeutic target.22 Figure 3: IFN-γ signaling pathway in PTPN2 deficient tumor cell. STAT1 remains phosphorylated and homodimerizes in order to enter the nucleus and induce the transcription of immune related genes. This ultimately leads to an increase in chemokines as well as CD8+ cells that reduce the size of the tumor. Berkeley Pharma Tech Journal of Medicine | 88 4. PTPN3 Nonsense and frameshift mutations in PTPN3 that hinder its phosphatase activity have been found in lung cancer tissue.23 Consequently, overexpression of PTPN3 results in reduced lung cancer cell growth and migration, indicating that it might have tumor suppressor capabilities.24,25 PTPN3 is capable of suppressing lung cancer cell invasion by dephosphorylating the protein, Src, at Tyr416, which inhibits Src- mediated phosphorylation of Tyr652 on another protein known as Dishevelled Associated Activator of Morphogenesis 1 (DAAM1).24 Tyrosine phosphorylation of DAAM 1 at Tyr652 by Src is needed for DAAM1 dimerization.24 In the absence of PTPN3, DAAM1 is able to dimerize, leading to long and thick actin, which improves cancer cell migration. PTPN3 knockdown cells moved 30% faster than the control which had normal expression of PTPN3.24 4.1 EGFR Additionally, PTPN3 is able to target EGFR for lysosomal degradation inhibiting proliferation of cancer cells. PTPN3 is capable of dephosphorylating EPS 15, which promotes the endocytosis of EGFR, given that EGFR is bound to its ligand, EGF.25 When EGFR is internalized via lipid raft-mediated endocytosis, it is either recycled back to the cell surface, targeted to the lysosome for degradation, or internalized to subcellular compartments.25 Thus, since PTPN3 is capable of causing EGFR to be degraded via its effects on Eps 15, PTPN3 functions as a tumor suppressor. Overexpression of PTPN3 resulted in a decrease of EGFR levels when stimulated by EGF.25 This confirmed dephosphorylation of Eps15 by PTPN3 is capable of suppressing tumor growth. 5. PTPN6 5.1 CRC Tissue PTPN6 was highly expressed in CRC tissue as demonstrated by qPCR, CCK-8, clone formation assay, and other assessments.26 The overexpression of PTPN6 in malignant colon cancer cells was associated with poor prognosis in colon cancer patients. Conversely, the inhibition of PTPN6 restrained migration, invasion, and clonogenics of CRC tissues.26 Therefore, PTPN6 amplification can potentially be used as a biomarker for CRC and its progression. PTPN 6 is a possible tumor promoter due to its ability to promote proliferation and migration of tumor cells. Additionally, PTPN6 interacts with EGFR, a receptor known to induce pathways Berkeley Pharma Tech Journal of Medicine | 89 involved in proliferation, migration, and adhesion. Increased expression of both PTPN6 and EGFR resulted in the greatest cancerous proliferation as compared to cells with only PTPN6 or EGFR overexpressed. Thus, either targeting PTPN6 or the PTPN6-EGFR complex with an inhibitor could be a potential therapeutic. However, other research suggests PTPN6 might have tumor suppressing capabilities by decreasing the levels of the protein SP1 (Specificity Protein 1). MAPK pathway is typically activated by SP1; however, due to PTPN6’s inhibition of SP1, MAPK pathway is consequently suppressed. PTPN6 inhibition promotes enhanced chemosensitivity within CRC cells. Yet, more research needs to be conducted in order to further understand the various effects of PTPN6 within CRC.27 6. PTPN11 6.1 Shp2 PTPN11 is a gene that encodes for Shp2, a protein consisting of two N-terminal Src homology (SH2) domains, a catalytic PTP domain, and a C- terminal tail with tyrosyl phosphorylation sites.28 Shp2/PTPN11 is involved in promoting signaling pathways such as Ras/ERK, RAS/MAPK, JAK/STAT, as well as KRAS signaling within the tumor microenvironment.28 Increased expression of Shp2/PTPN11 is associated with a 5.34 fold increase in risk for gastric cancer and a 2.95 fold increase in risk for lung cancer.29 Furthermore, other studies have found Shp2 to be highly expressed in 60.78% of gastric cancer and 70% of NSCLC tissue samples.29 Patients infected with Helicobacter pylori are at a greater risk for gastric cancer.30 A virulence factor of H. pylori known as Cytotoxin associated antigen (CagA) is able to interact with the epithelial gastric cells, leading to the Src-dependent tyrosine phosphorylation of CagA.30 The phosphorylated CagA binds with Shp2, forming a complex that allows for the transition of Shp2 into its active form. In its active form, Shp2 is capable of inducing oncogenic properties, such as neoplasia, gastric atrophy, and increased migration of gastric epithelial cells.30 In contrast, in many cases of lung cancer, a missense mutation in the PTPN11 gene leads to a dysfunctional Shp2 protein that results in inappropriate activation of various signal transduction pathways.31 Due to the proto-oncogenic nature of PTPN11, various strides have been made in developing small molecule inhibitors which are capable of binding to the catalytic site of Shp2. One potential inhibitor, SHP099, is able to bind to the N-terminal, C- Berkeley Pharma Tech Journal of Medicine | 90 terminal and PTP domain on SHP2, resulting in increased immune system activity such as greater IFN-γ signaling. This induced greater transcription of cytotoxic T- cell related genes within a mice model for lung cancer treatment.31 While most of Shp2 inhibitors are in the preclinical study stages, the potential of PTPN11 as a therapeutic drug target is a promising prospect in treating many types of cancers, including gastric and lung cancer. 7. PTPN12 PTPN12 is a tumor suppressor that normally has an inhibitory effect on the Ras/MEK/ERK signaling by dephosphorylating the protein Shc.32 However, it was hypothesized that a missense mutation in PTPN12 would leave Shc phosphorylated, resulting in hallmarks of cancer, such as cellular proliferation and increased migration.33 For example, researchers identified that a variant of PTPN12 (rs3750050 G allele) increased the risk of CRC by 19%.33 Conversely, upregulation of PTPN12 has been correlated with incidences of esophageal carcinoma, stomach adenocarcinoma and colorectal cancer, making it a highly favorable candidate for biomarker.34 The researchers acknowledge that these findings are seemingly in contradiction with previous literature that suggests PTPN12 to have tumor suppressing capabilities.34 Another study showed that PTPN12 might be a favorable prognosis marker for NSCLC in patients due to higher expression levels associated with higher 5-year survival rates, especially within the subgroup with non-squamous cell carcinoma.35 Due to the non-definitive role of PTPN12, further research still needs to be conducted.33-35 8. PTPN13 Like many of the other PTPNs previously discussed, PTPN13 has been shown to have both tumor suppressive and tumor promoting roles depending on the cancer being examined.36 PTPN13 was shown to act as a tumor suppressor in breast cancer37 and high grade serous ovarian carcinoma.38 Likewise, in lung cancer, PTPN13 has been shown to have tumor suppressor capabilities by acting on various pathways.38-42 PTPN13 is downregulated in lung cancer mainly due to a loss of at least one copy of the PTPN13 locus at chromosome 4q.40 40% of cases are not accounted for by this mechanism, however, and further research is needed to understand how it is downregulated in those cases.40 Various studies have shown that PTPN13 Berkeley Pharma Tech Journal of Medicine | 91 downregulation results in increased proliferation of NSCLC [39-41] in addition to greater tumor cell size.40 To further confirm the role of PTPN13, PTPN13 expression was restored to PTPN13 knockdown cells and this resulted in slower proliferation of NSCLC.40 PTPN13’s tumor suppressing capabilities stem from it inhibiting various oncogenic pathways. This is explored through the use of microRNAs which are known to have different effects on LUAD proliferation. For example, miR-36143 and miR-34044 inhibit LUAD cell growth while miR-48345 and miR-22446 promote LUAD cell growth. MicroRNA-30e-5p (miR-30e) is of interest to this review paper due to its ability to downregulate PTPN13 [Figure 4B]. Knockdown of miR-30e suppresses LUAD growth, suggesting that the presence of miR-30e is indicative of poor prognosis.39 Upregulation of PTPN13 counteracts the tumor promoting effects of miR-30e by inhibiting EGFR/AKT signaling.39 PTPN13 was also shown to inhibit the Src/ERK/YAP1 signaling pathway, further contributing to its tumor suppressive properties in lung cancer. YAP1 promotes the proliferation of NSCLC cells, classifying it as an oncoprotein.42,47 YAP1 has also been shown to activate the MEK/ERK pathway by promoting the expression of FGF239 [Figure 4A]. Nuclear YAP1 levels were increased in PTPN13 knockdown cells, indicating that PTPN13 might act to inhibit YAP1. It is also thought that YAP1 could be upregulated via the MEK/ERK pathway when PTPN13 is suppressed.42 Thus, another pathway by which PTPN13 acts as a tumor suppressor is by inhibiting the MEK/ERK pathway, which suppresses the upregulation of YAP1. Various cancers, including lung cancer, have been shown to have higher than normal levels of HER2, indicating that upregulation of HER2 leads to tumor growth and poor prognosis. PTPN13 downregulates HER2 activity by dephosphorylating the cytoplasmic domain of HER2, possibly decreasing the metastasis associated with HER2-overactive NSCLC tumor cells.41 PTPN13 was also found to dephosphorylate EGFR.40 Downregulation of PTPN13 increased EGF-stimulated EGFR and HER2 phosphorylation, leading to increased activation of MAPK and Akt dependent pathways.40 Berkeley Pharma Tech Journal of Medicine | 92 Figure 4: Overview of PTPN13’s effect on various pathways. PTPN13 has been shown to work by affecting the MEK/ERK pathway in different ways. A) PTPN13 can downregulate EGFR and HER2 receptors by dephosphorylating them [40]. YAP1 levels decrease in the presence of PTPN13, which could be due to PTPN13 inhibiting the MEK/ ERK pathway. B) miR-30e is capable of downregulating PTPN13, resulting in increased cell growth in LUAD by promoting EGFR/AKT signaling. 9. Current Clinical Trials There are ongoing clinical trials exploring the efficacy of small molecule inhibitors on PTPN11, like JAB-3068 and JAB-3312, in patients with advanced solid tumors. It is hypothesized that these small molecules will prevent various oncogenic phenotypes associated with hyperactivation of Shp2 mediated signal transduction pathways. JAB-3068 is currently in Phase 1/2a and is recruiting patients with advanced solid tumors of NSCLC, head and neck cancer, esophageal cancer, and other metastatic solid tumors.49 The experiment will consist of oral administration of JAB-3068 every morning after a six hour fast.49 A pharmacokinetics (PK) analysis will be taken which will be used to monitor the drug as it reacts with the body. Similarly, the small molecule inhibitor JAB-3312 is in Phase 1 Study and is also recruiting patients with advanced solid tumors of NSCLC, CRC, pancreatic ductal carcinoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, breast cancer, and other solid tumors. The experiment will consist of daily oral administration of the drug in treatment cycles of 21 days.50 9.1 Matched Targeted Therapy Another ongoing clinical trial is utilizing Matched Targeted Therapy (MTT) in order to test the efficacy of Trametinib on PTPN11 and other proteins involved in Berkeley Pharma Tech Journal of Medicine | 93 cancer progression. Specifically, Trametinib is a kinase inhibitor that blocks the abnormal protein signals that cause cancer cell multiplication. The drug will be consumed orally with two mg per day. The trials are expected to be completed by 2026. Some measures that researchers will be noting are short-term and long-term progression, duration of response, survival, adverse effects, and more.51 10. Future Directions & Conclusion This article provided a review of various PTPN protein families in regards to lung and digestive cancer with the goal of providing researchers foundational information in their efforts to develop therapeutics that target PTPNs. Many studies have investigated the roles of PTPNs in tumor progression, outlining how PTPNs act on different pathways and thus affect tumor progression differently. This review paper focuses on the molecular mechanisms that underlie the effects of PTPNs, as it could aid in determining if PTPN therapeutics are worth exploring. Many of these PTPNs can be used as biomarkers and/or prognosis markers as overexpression or underexpression of certain PTPNs are associated with each cancer [Figure 5]. In regards to digestive cancer, PTPN2 and PTPN11 were shown to have tumor promoting capabilities while PTP1B, PTPN6, and PTPN12 were shown to have both tumor promoting and tumor suppressing capabilities. In lung cancer, PTPN3, PTPN12, and PTPN13 were shown to have tumor suppressing capabilities while PTPN11 had tumor promoting capabilities. PTP1B was seen to have both tumor suppressing and tumor promoting capabilities depending on the cellular substrate. Given these PTPNs and their varying effects on each cancer, therapeutic targets that act to either promote or suppress various PTPN have great potential for cancer treatment. To suppress PTPNs with tumor promoting capabilities, researchers could look into developing inhibitors that bind to the PTPN proteins. In contrast, in order to promote PTPNs with tumor suppressing capabilities, researchers could look at developing transcription factors that enhance PTPN gene expression. Therefore, additional clinical trials and research need to be conducted in order to better understand how to mechanistically target PTPNs to develop effective treatments for lung and digestive cancer. Berkeley Pharma Tech Journal of Medicine | 94 PTPN Member Lung Cancer Digestive Cancer PTPN1/PTP1B Biomarker: Increased levels of PTP1B in NSCLC; decreased levels of PTPN1 in LUAD Therapeutic: Inhibition of PTP1B in NSCLC Biomarker: Increased levels of PTP1B in CRC, gastric cancer Therapeutic: Inhibition of PTP1B blocks Shc-Grb2-SOS pathway and MEK/Erk pathway Contrasting: Tumor suppressor qualities based on cellular context PTPN2 Insufficient Research Biomarker: Increased levels of PTPN2 across all stages of CRC Therapeutic: Inhibition of PTPN2 which could increase IFN-γ signaling pathway and suppress KRAS- mediated MAPK pathway PTPN3 Biomarker: Decreased levels of PTPN3 in lung cancer tissue Therapeutic: Upregulation of PTPN3 to allow for the dephosphorylation of Src and targeting of EGFR for lysosomal degradation Insufficient Research PTPN6 Insufficient Research Biomarker: Increased levels of PTPN6 in CRC Therapeutic: Inhibition of PTPN6- SP1-MAPK pathway to increase chemosensitivity of tumor cells; Inhibition of PTPN6-EGFR complex Berkeley Pharma Tech Journal of Medicine | 95 PTPN11 Biomarker: Increased levels of PTPN11/Shp2 in 70% of NSCLC tissue samples Therapeutic: Small molecule inhibition of PTPN11/Shp2 which prevents Shp2 mediated signal transduction pathways that are hyperactivated Biomarker: Increased levels of PTPN11/Shp2 in 60.78% of gastric cancers Therapeutic: Small molecule inhibition of PTPN11/Shp2 which prevents Shp2 mediated signal transduction pathways that are hyperactivated PTPN12 Prognosis Marker: Increased levels of PTPN12 are associated with higher 5- year survival rates in NSCLC Biomarker: Increased levels of PTPN12 are correlated with incidences of digestive cancers Contrasting: Other research has shown PTPN12 as a tumor suppressor that normally has an inhibitory effect on the Ras/MEK/ERK signaling by dephosphorylating the protein Shc PTPN13 Biomarker: Decreased levels in NSCLC Therapeutic: Upregulation of PTPN13 to inhibit the Src/ERK/YAP1 signaling pathway, counteract the effects of miR-30e, and to downregulate HER2 activity Insufficient Research Figure 5: Summary of PTPN families and their potential as a biomarker, prognosis marker, and or/ therapeutic target in lung and digestive cancer. 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