Bone metastatic prostate cancer and resistance to tyrosine kinase inhibitors: an intimate relationship between loss of miR-203 and up-regulation of EGFR signaling

A tumor suppressor role for miR-203 in RAS-dependent prostate cancer metastasis has been described recently by our group. We have explored the regulatory mechanisms by which miR-203 is being regulated through EGFR signaling. We investigated the molecular mechanism of metastasis and identified novel roles of genes that interact with miR-203 downstream of activated Ras. We showed an amplifying regulatory loop involving the direct interaction of miR-203 with the EGFR ligands, AREG, EREG, and TGFA 3’UTR. Using clinical specimens and database analysis, our data suggested that decreasing miR-203 and increasing EGFR ligands, AREG, EREG, and TGFA expressions are correlated with prostate cancer progression. Since tyrosine kinase inhibitors (TKIs) have been shown to inhibit tyrosine phosphorylation of EGFR in a dose-dependent manner, we examined a role for miR-203 in TKIs-induced apoptosis in RAS-activated prostate cancer. We investigated the mechanisms by which miR-203 overexpression contributes to TKIs-resistant RAS-activated prostate cancer cells apoptosis. We have shown indications for candidate miR-203 targets that are either influenced by anti-apoptotic proteins (e.g. API5, BIRC2, and TRIAP1) or positively influenced by a novel NF-κB-inducible oncogenic molecule, TNFAIP8. These observations suggest that the latter category may be synergistically affected by the regulatory loop of miR-203 depletion and anti-apoptotic proteins overexpression. Our results provided evidence showing a role of miR-203 in regulating the expression of EGFR signaling genes in response to TKIs-resistance during prostate cancer progression

Bone metastatic prostate cancer and resistance to tyrosine kinase inhibitors: an intimate relationship between loss of miR-203 and up-regulation of EGFR signaling: DOI: 10.14800/rd.345

A tumor suppressor role for miR-203 in RAS-dependent prostate cancer metastasis has been described recently by our group. We have explored the regulatory mechanisms by which miR-203 is being regulated through EGFR signaling. We investigated the molecular mechanism of metastasis and identified novel roles of genes that interact with miR-203 downstream of activated Ras. We showed an amplifying regulatory loop involving the direct interaction of miR-203 with the EGFR ligands, AREG, EREG, and TGFA 3’UTR. Using clinical specimens and database analysis, our data suggested that decreasing miR-203 and increasing EGFR ligands, AREG, EREG, and TGFA expressions are correlated with prostate cancer progression. Since tyrosine kinase inhibitors (TKIs) have been shown to inhibit tyrosine phosphorylation of EGFR in a dose-dependent manner, we examined a role for miR-203 in TKIs-induced apoptosis in RAS-activated prostate cancer. We investigated the mechanisms by which miR-203 overexpression contributes to TKIs-resistant RAS-activated prostate cancer cells apoptosis. We have shown indications for candidate miR-203 targets that are either influenced by anti-apoptotic proteins (e.g. API5, BIRC2, and TRIAP1) or positively influenced by a novel NF-?B-inducible oncogenic molecule, TNFAIP8. These observations suggest that the latter category may be synergistically affected by the regulatory loop of miR-203 depletion and anti-apoptotic proteins overexpression. Our results provided evidence showing a role of miR-203 in regulating the expression of EGFR signaling genes in response to TKIs-resistance during prostate cancer progression

ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer

Prostate cancer (PCa) is the second most common killer among men in Western countries. Targeting androgen receptor (AR) signaling by androgen deprivation therapy (ADT) is the current therapeutic regime for patients newly diagnosed with metastatic PCa. However, most patients relapse and become resistant to ADT, leading to metastatic castration-resistant PCa (CRPC) and eventually death. Several proposed mechanisms have been proposed for CRPC; however, the exact mechanism through which CRPC develops is still unclear. One possible pathway is that the AR remains active in CRPC cases. Therefore, understanding AR signaling networks as primary PCa changes into metastatic CRPC is key to developing future biomarkers and therapeutic strategies for PCa and CRPC. In the current review, we focused on three novel biomarkers (ZBTB46, SPDEF, and ETV6) that were demonstrated to play critical roles in CRPC progression, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) drug resistance, and the epithelial-to-mesenchymal transition (EMT) for patients treated with ADT or AR inhibition. In addition, we summarize how these potential biomarkers can be used in the clinic for diagnosis and as therapeutic targets of PCa

Correction: Fararjeh, A-F S., et al. ZBTB46, SPDEF, ETV6 Novel Potential Biomarkers and Therapeutic Targets in Castration Resistance Prostate Cancer. Int. J. Mol. Sci. 2019, 20, 2802

The authors wish to make the following correction to this paper [...

Interplay of Epidermal Growth Factor Receptor and Signal Transducer and Activator of Transcription 3 in Prostate Cancer: Beyond Androgen Receptor Transactivation

Prostate cancer (PCa) is one of the most common cancers in the world and causes thousands of deaths every year. Conventional therapy for PCa includes surgery and androgen deprivation therapy (ADT). However, about 10–20% of all PCa cases relapse; there is also the further development of castration resistant adenocarcinoma (CRPC-Adeno) or neuroendocrine (NE) PCa (CRPC-NE). Due to their androgen-insensitive properties, both CRPC-Adeno and CRPC-NE have limited therapeutic options. Accordingly, this study reveals the inductive mechanisms of CRPC (for both CRPC-Adeno and CRPC-NE) and fulfils an urgent need for the treatment of PCa patients. Although previous studies have illustrated the emerging roles of epidermal growth factor receptors (EGFR), signal transducer, and activator of transcription 3 (STAT3) signaling in the development of CRPC, the regulatory mechanisms of this interaction between EGFR and STAT3 is still unclear. Our recent studies have shown that crosstalk between EGFR and STAT3 is critical for NE differentiation of PCa. In this review, we have collected recent findings with regard to the involvement of EGFR and STAT3 in malignancy progression and discussed their interactions during the development of therapeutic resistance for PCa

Adaptation of Land-Use Demands to the Impact of Climate Change on the Hydrological Processes of an Urbanized Watershed

The adaptation of land-use patterns is an essential aspect of minimizing the inevitable impact of climate change at regional and local scales; for example, adapting watershed land-use patterns to mitigate the impact of climate change on a region’s hydrology. The objective of this study is to simulate and assess a region’s ability to adapt to hydrological changes by modifying land-use patterns in the Wu-Du watershed in northern Taiwan. A hydrological GWLF (Generalized Watershed Loading Functions) model is used to simulate three hydrological components, namely, runoff, groundwater and streamflow, based on various land-use scenarios under six global climate models. The land-use allocations are simulated by the CLUE-s model for the various development scenarios. The simulation results show that runoff and streamflow are strongly related to the precipitation levels predicted by different global climate models for the wet and dry seasons, but groundwater cycles are more related to land-use. The effects of climate change on groundwater and runoff can be mitigated by modifying current land-use patterns; and slowing the rate of urbanization would also reduce the impact of climate change on hydrological components. Thus, land-use adaptation on a local/regional scale provides an alternative way to reduce the impacts of global climate change on local hydrology

MicroRNAs as clinical tools for diagnosis, prognosis, and therapy in prostate cancer

Prostate cancer (PCa) is one of the most commonly diagnosed cancers among men worldwide. Despite the presence of accumulated clinical strategies for PCa management, limited prognostic/sensitive biomarkers are available to follow up on disease occurrence and progression. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression through post-transcriptional regulation of their complementary target messenger RNA (mRNA). MiRNAs modulate fundamental biological processes and play crucial roles in the pathology of various diseases, including PCa. Multiple evidence proved an aberrant miRNA expression profile in PCa, which is actively involved in the carcinogenic process. The robust and pleiotropic impact of miRNAs on PCa suggests them as potential candidates to help more understand the molecular landscape of the disease, which is likely to provide tools for early diagnosis and prognosis as well as additional therapeutic strategies to manage prostate tumors. Here, we emphasize the most consistently reported dysregulated miRNAs and highlight the contribution of their altered downstream targets with PCa hallmarks. Also, we report the potential effectiveness of using miRNAs as diagnostic/prognostic biomarkers in PCa and the high-throughput profiling technologies that are being used in their detection. Another key aspect to be discussed in this review is the promising implication of miRNAs molecules as therapeutic tools and targets for fighting PCa

Self-renewing Pten-/- TP53-/- protospheres produce metastatic adenocarcinoma cell lines with multipotent progenitor activity.

Prostate cancers of luminal adenocarcinoma histology display a range of clinical behaviors. Although most prostate cancers are slow-growing and indolent, a proportion is aggressive, developing metastasis and resistance to androgen deprivation treatment. One hypothesis is that a portion of aggressive cancers initiate from stem-like, androgen-independent tumor-propagating cells. Here we demonstrate the in vitro creation of a mouse cell line, selected for growth as self-renewing stem/progenitor cells, which manifests many in vivo properties of aggressive prostate cancer. Normal mouse prostate epithelium containing floxed Pten and TP53 alleles was subjected to CRE-mediated deletion in vitro followed by serial propagation as protospheres. A polyclonal cell line was established from dissociated protospheres and subsequently a clonal daughter line was derived. Both lines demonstrate a mature luminal phenotype in vitro. The established lines contain a stable minor population of progenitor cells with protosphere-forming ability and multi-lineage differentiation capacity. Both lines formed orthotopic adenocarcinoma tumors with metastatic potential to lung. Intracardiac inoculation resulted in brain and lung metastasis, while intra-tibial injection induced osteoblastic bone formation, recapitulating the bone metastatic phenotype of human prostate cancer. The cells showed androgen receptor dependent growth in vitro. Importantly, in vivo, the deprivation of androgens from established orthotopic tumors resulted in tumor regression and eventually castration-resistant growth. These data suggest that transformed prostate progenitor cells preferentially differentiate toward luminal cells and recapitulate many characteristics of the human disease

Disruption of ETV6 leads to TWIST1-dependent progression and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in prostate cancer

Abstract Background ETS variant gene 6 (ETV6) is a putative tumor suppressor and repressed by epidermal growth factor receptor (EGFR) signaling in prostate cancer. Since EGFR antagonists seem ineffective in castration-resistant prostate cancer (CRPC), we aim to study the role of ETV6 in the development of drug resistance. Methods Etv6 target gene was validated by ChIP and promoter reporter assays. Correlation of ETV6 and TWIST1 was analyzed in human clinical datasets and tissue samples. Migration, invasion, and metastasis assays were used to measure the cellular responses after perturbation of ETV6 -TWIST1 axis. Proliferation and tumor growth in xenograft model were performed to evaluate the drug sensitivities of EGFR-tyrosine kinase inhibitors (TKIs). Results ETV6 inhibits TWIST1 expression and disruption of ETV6 promotes TWIST1-dependent malignant phenotypes. Importantly, ETV6 is required to the anti-proliferation effects of EGFR-TKIs, partly due to the inhibitory function of ETV6 on TWIST1. We also found that EGFR-RAS signaling is tightly controlled by ETV6, supporting its role in TKI sensitivity. Conclusions Our study demonstrates that disruption of ETV6 contributes to EGFR-TKI resistance, which is likely due to derepression of TWIST1 and activation of EGFR-RAS signaling. Our results implicate ETV6 as a potential marker for predicting efficacy of an EGFR-targeted anticancer approach. Combination treatment of TWIST1 inhibitors could sensitize the anti-proliferation effects of EGFR-TKIs