Translocation of protein tyrosine phosphatase Pez/PTPD2/PTP36 to the nucleus is associated with induction of cell proliferation

Pez is a non-transmembrane tyrosine phosphatase with homology to the FERM (4.1, ezrin, radixin, moesin) family of proteins. The subcellular localisation of Pez in endothelial cells was found to be regulated by cell density and serum concentration. In confluent monolayers Pez was cytoplasmic, but in cells cultured at low density Pez was nuclear, suggesting that it is a nuclear protein in proliferating cells. This notion is supported by the loss of nuclear Pez when cells are serum-starved to induce quiescence, and the rapid return of Pez to the nucleus upon refeeding with serum to induce proliferation. Vascular endothelial cells normally exist as a quiescent confluent monolayer but become proliferative during angiogenesis or upon vascular injury. Using a 'wound' assay to mimic these events in vitro, Pez was found to be nuclear in the cells that had migrated and were proliferative at the 'wound' edge. TGFbeta, which inhibits cell proliferation but not migration, inhibited the translocation of Pez to the nucleus in the cells at the 'wound' edge, further strengthening the argument that Pez plays a role in the nucleus during cell proliferation. Together, the data presented indicate that Pez is a nuclear tyrosine phosphatase that may play a role in cell proliferation.Carol Wadham, Jennifer R. Gamble, Mathew A. Vadas and Yeesim Khew-Goodal

PTPN14 (protein tyrosine phosphatase, non-receptor type 14)

Review on PTPN14 (protein tyrosine phosphatase, non-receptor type 14), with data on DNA, on the protein encoded, and where the gene is implicated

MicroRNA-9 as Potential Biomarker for Breast Cancer Local Recurrence and Tumor Estrogen Receptor Status

MicroRNAs (miRs) are small, non-protein coding transcripts involved in many cellular functions. Many miRs have emerged as important cancer biomarkers. In the present study, we investigated whether miR levels in breast tumors are predictive of breast cancer local recurrence (LR). Sixty-eight women who were diagnosed with breast cancer at the Lombardi Comprehensive Cancer Center were included in this study. Breast cancer patients with LR and those without LR were matched on year of surgery, age at diagnosis, and type of surgery. Candidate miRs were identified by screening the expression levels of 754 human miRs using miR arrays in 16 breast tumor samples from 8 cases with LR and 8 cases without LR. Eight candidate miRs that showed significant differences between tumors with and without LR were further verified in 52 tumor samples using real-time PCR. Higher expression of miR-9 was significantly associated with breast cancer LR in all cases as well as the subset of estrogen receptor (ER) positive cases (p = 0.02). The AUCs (Area Under Curve) of receiver operating characteristic (ROC) curves of miR-9 for all tumors and ER positive tumors are 0.68 (p = 0.02) and 0.69 (p = 0.02), respectively. In ER positive cases, Kaplan-Meier analysis showed that patients with lower miR-9 levels had significantly better 10-year LR-free survival (67.9% vs 30.8%, p = 0.02). Expression levels of miR-9 and another miR candidate, miR-375, were also strongly associated with ER status (p<0.001 for both). The potential of miR-9 as a biomarker for LR warrants further investigation with larger sample size

Identification of miRs-143 and -145 that Is Associated with Bone Metastasis of Prostate Cancer and Involved in the Regulation of EMT

The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bone. MicroRNAs (miRNAs) play a crucial role in many tumor metastases. The importance of miRNAs in bone metastasis of PCa has not been elucidated to date. We investigated whether the expression of certain miRNAs was associated with bone metastasis of PCa. We examined the miRNA expression profiles of 6 primary and 7 bone metastatic PCa samples by miRNA microarray analysis. The expression of 5 miRNAs significantly decreased in bone metastasis compared with primary PCa, including miRs-508-5p, -145, -143, -33a and -100. We further examined other samples of 16 primary PCa and 13 bone metastases using real-time PCR analysis. The expressions of miRs-143 and -145 were verified to down-regulate significantly in metastasis samples. By investigating relationship of the levels of miRs-143 and -145 with clinicopathological features of PCa patients, we found down-regulations of miRs-143 and -145 were negatively correlated to bone metastasis, the Gleason score and level of free PSA in primary PCa. Over-expression miR-143 and -145 by retrovirus transfection reduced the ability of migration and invasion in vitro, and tumor development and bone invasion in vivo of PC-3 cells, a human PCa cell line originated from a bone metastatic PCa specimen. Their upregulation also increased E-cadherin expression and reduced fibronectin expression of PC-3 cells which revealed a less invasive morphologic phenotype. These findings indicate that miRs-143 and -145 are associated with bone metastasis of PCa and suggest that they may play important roles in the bone metastasis and be involved in the regulation of EMT Both of them may also be clinically used as novel biomarkers in discriminating different stages of human PCa and predicting bone metastasis

Myc-modulated miR-9 makes more metastases

The microRNA miR-9 is induced by Myc in breast cancer cells where it targets the major epithelial adherens junction protein, E-cadherin. This primes the cancer cells for epithelial-mesenchymal transition (EMT) and also stimulates angiogenesis in tumours.Yeesim Khew-Goodall and Gregory J. Goodal

A microRNA that limits metastatic colonisation and endothelial recruitment

For a cancer to metastasise, it must overcome the physiological mechanisms that normally protect against the dissemination of cells and their lodgement and growth at remote sites. The mechanisms by which invading cancer cells modify and engage with the new environment at a secondary site are poorly understood but provide potential novel avenues for therapeutic intervention. A recent report in Nature (Png et al, 2012) identifies a microRNA, miR-126, whose loss in tumour cells promotes the initiation of metastases in various secondary organs. The key targets of miR-126 in this process are found to be novel regulators of endothelial cell recruitment and angiogenesis. © 2012 European Molecular Biology Organization | All Rights Reserved.Yeesim Khew-Goodall and Gregory J Goodal

Network-based approaches to understand the roles of miR-200 and other micrornas in cancer

microRNAs (miRNA) are well suited to the task of regulating gene expression networks, because any given miRNA has the capacity to target dozens, if not hundreds, of genes. The simultaneous targeting of multiple genes within a pathway may enable miRNAs to more strongly regulate the pathway, or to achieve more subtle control through the targeting of distinct subnetworks of genes. Therefore, as our capacity to discover miRNA targets en masse increases, so must our consideration of the complex networks in which these genes participate. We highlight recent studies in which the comprehensive identification of targets has been used to elucidate miRNA-regulated gene networks in cancer, focusing especially upon miRNAs such as members of the miR-200 family that regulate epithelial-mesenchymal transition (EMT), a reversible phenotypic switch whereby epithelial cells take on the more invasive properties of their mesenchymal counterparts. These studies have expanded our understanding of the roles of miRNAs in EMT, which were already known to form important regulatory loops with key transcription factors to regulate the epithelial or mesenchymal properties of cells. Cancer Res; 75(13); 2594-9. ©2015 AACR.Cameron P. Bracken, Yeesim Khew-Goodall and Gregory J. Goodal

PTP-Pez: A novel regulator of TGF beta signaling

© 2008 Landes BioscienceThe TGF-betas are a family of pleiotropic cytokines that mediate diverse effects including the regulation of cell cycle progression, apoptosis, tissue remodelling and epithelial-mesenchymal transition (EMT). These diverse effects allow the TGF-betas to play multiple and even opposing roles in different contexts during embryonal development, tissue homeostasis and cancer progression. We recently reported that the protein tyrosine phosphatase Pez is a novel inducer of TGF-beta signaling, regulating EMT and organogenesis in developing zebrafish embryos, and leading to TGF-beta mediated EMT when over-expressed in vitro in epithelial MDCK cells. A number of mutations in Pez have been shown to be associated with breast and colorectal cancers, although the effect of these mutations on Pez function and their contribution to cancer progression remains unclear. Our finding that Pez regulates TGF-beta signaling is therefore of interest not only in the context of identifying a novel upstream regulator of TGF-beta signaling, but also in implicating the dysregulation of TGF-beta signaling as a possible link between Pez mutation and cancer progression. Here we discuss the implications of our research, in the context of dysregulation of TGF-beta signaling in cancer and other human pathologies.Leila Wyatt and Yeesim Khew-Goodal

The role of microRNAs in metastasis and epithelial-mesenchymal transition

© 2009 Springer. Part of Springer Science+Business MediaFor a tumour cell to metastasise it must successfully negotiate a number of events, requiring a series of coordinated changes in the expression of many genes. MicroRNAs are small non-coding RNA molecules that post-transcriptionally control gene expression. As microRNAs are now recognised as master regulators of gene networks and play important roles in tumourigenesis, it is no surprise that microRNAs have recently been demonstrated to have central roles during metastasis. Recent work has also demonstrated critical roles for microRNAs in epithelial-mesenchymal transition, a phenotypic change underlain by altered gene expression patterns that is believed to mirror events in metastatic progression. These findings offer new potential for improved prognostics through expression profiling and may represent novel molecular treatment targets for future therapy. In this review, we summarise the multistep processes of metastasis and epithelial-mesenchymal transition and describe the recent discoveries of microRNAs that participate in controlling these processes.C. P. Bracken, P. A. Gregory, Y. Khew-Goodall, and G. J. Goodal

Aberrant post-translational modifications in endosomal trafficking are potential therapeutic targets to avert therapy resistance in solid cancers: Dysregulation of PTM-regulated endosomal interactions presents an opportunity to block oncogenic signalling from multiple receptors by targeting common trafficking pathways

First published: 16 December 2021Drugs targeting a single TK/RTK in the treatment of solid cancers has not had the same success seen in blood cancers. This is, in part, due to acquired resistance in solid cancers arising from a range of mechanisms including the upregulation of compensatory RTK signalling. Rather than attempting to inhibit individual compensatory RTK—requiring knowledge of which RTKs are upregulated in any given tumour—strategies to universally inhibit signalling from multiple RTKs may represent an effective alternative. Endosomal trafficking of RTKs is a common conduit that can regulate signalling from multiple RTKs simultaneously. As such, we posit that targeting endosomal trafficking—in particular, aberrant post-translational modifications in cancers that contribute to dysregulated endosomal trafficking—could inhibit oncogenic signalling driven by multiple RTKs and pave the way for the development of a novel class of inhibitors that shift the trafficking of RTKs to inhibit tumour growth.Winona Onglao, Yeesim Khew-Goodall, Leila Belle, Ana Loni