Publications by authors named "Cristian Rodriguez-Aguayo"

116 Publications

Targeting CDK7 reverses tamoxifen resistance through regulating stemness in ER+ breast cancer.

Pharmacol Rep 2022 Jan 9. Epub 2022 Jan 9.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Background: Although tamoxifen is the mainstay endocrine therapy for estrogen receptor-positive (ER+) breast cancer patients, the emergence of tamoxifen resistance is still the major challenge that results in treatment failure. Tamoxifen is very effective in halting breast cancer cell proliferation; nonetheless, the ability of tamoxifen to target cancer stem and progenitor cell populations (CSCs), a major key player for the emergence of tamoxifen resistance, has not been adequately investigated yet. Thus, we explored whether targeting CDK7 modulates CSCs subpopulation and tamoxifen resistance in ER+ breast cancer cells.

Methods: Mammosphere-formation assay, stem cell biomarkers and tamoxifen sensitivity were analyzed in MCF7 tamoxifen-sensitive cell line and its resistant counterpart, LCC2, following CDK7 targeting by THZ1 or siRNA.

Results: Analysis of clinically relevant data indicated that expression of stemness factor, SOX2, was positively correlated with CDK7 expression in tamoxifen-treated patients. Moreover, overexpression of the stemness gene, SOX2, was associated with shorter overall survival in those patients. Importantly, the number of CSC populations and the expression of CDK7, P-Ser118-ER-α and c-MYC were significantly higher in LCC2 cells compared with parental MCF-7 cells. Moreover, targeting CDK7 inhibited mammosphere formation, CSC-regulating genes, and CSC biomarkers expression in MCF-7 and LCC2 cells.

Conclusion: Our data indicate, for the first time, that CDK7-targeted therapy in ER+ breast cancer ameliorates tamoxifen resistance, at least in part, by inhibiting cancer stemness. Thus, targeting CDK7 might represent a potential approach for relieving tamoxifen resistance in ER+ breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s43440-021-00346-9DOI Listing
January 2022

RNA-binding protein FXR1 drives cMYC translation by recruiting eIF4F complex to the translation start site.

Cell Rep 2021 11;37(5):109934

Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Medical College of Wisconsin Cancer Center, Milwaukee, WI 53226, USA. Electronic address:

Fragile X-related protein-1 (FXR1) gene is highly amplified in patients with ovarian cancer, and this amplification is associated with increased expression of both FXR1 mRNA and protein. FXR1 expression directly associates with the survival and proliferation of cancer cells. Surface sensing of translation (SUnSET) assay demonstrates that FXR1 enhances the overall translation in cancer cells. Reverse-phase protein array (RPPA) reveals that cMYC is the key target of FXR1. Mechanistically, FXR1 binds to the AU-rich elements (ARE) present within the 3' untranslated region (3'UTR) of cMYC and stabilizes its expression. In addition, the RGG domain in FXR1 interacts with eIF4A1 and eIF4E proteins. These two interactions of FXR1 result in the circularization of cMYC mRNA and facilitate the recruitment of eukaryotic translation initiation factors to the translation start site. In brief, we uncover a mechanism by which FXR1 promotes cMYC levels in cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8675433PMC
November 2021

Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models.

Mol Cancer Ther 2021 Dec 28;20(12):2352-2361. Epub 2021 Sep 28.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen and Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group ( < 0.04 and < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules ( = 0.006) and markedly lower tumor weight compared with the control group ( = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-21-0370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643313PMC
December 2021

Assessment of In Vivo siRNA Delivery in Cancer Mouse Models.

Methods Mol Biol 2021 ;2372:157-168

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA.

RNA interference (RNAi) has rapidly become a powerful tool for target discovery and therapeutics. Small interfering RNAs (siRNAs) are highly effective in mediating sequence-specific gene silencing. However, the major obstacle for using siRNAs for cancer therapeutics is their systemic delivery from the administration site to target cells in vivo. This chapter describes approaches to deliver siRNA effectively for cancer treatment and discusses in detail the current methods to assess pharmacokinetics and biodistribution of siRNAs in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-0716-1697-0_14DOI Listing
January 2022

CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance.

Cell Rep 2021 08;36(7):109549

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) is mediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422976PMC
August 2021

Explainable Artificial Intelligence Reveals Novel Insight into Tumor Microenvironment Conditions Linked with Better Prognosis in Patients with Breast Cancer.

Cancers (Basel) 2021 Jul 9;13(14). Epub 2021 Jul 9.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

We investigated the data-driven relationship between immune cell composition in the tumor microenvironment (TME) and the ≥5-year survival rates of breast cancer patients using explainable artificial intelligence (XAI) models. We acquired TCGA breast invasive carcinoma data from the cbioPortal and retrieved immune cell composition estimates from bulk RNA sequencing data from TIMER2.0 based on EPIC, CIBERSORT, TIMER, and xCell computational methods. Novel insights derived from our XAI model showed that B cells, CD8 T cells, M0 macrophages, and NK T cells are the most critical TME features for enhanced prognosis of breast cancer patients. Our XAI model also revealed the inflection points of these critical TME features, above or below which ≥5-year survival rates improve. Subsequently, we ascertained the conditional probabilities of ≥5-year survival under specific conditions inferred from the inflection points. In particular, the XAI models revealed that the B cell fraction (relative to all cells in a sample) exceeding 0.025, M0 macrophage fraction (relative to the total immune cell content) below 0.05, and NK T cell and CD8 T cell fractions (based on cancer type-specific arbitrary units) above 0.075 and 0.25, respectively, in the TME could enhance the ≥5-year survival in breast cancer patients. The findings could lead to accurate clinical predictions and enhanced immunotherapies, and to the design of innovative strategies to reprogram the breast TME.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13143450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303703PMC
July 2021

Inactivating Mutations of the Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy.

Cancers (Basel) 2021 May 20;13(10). Epub 2021 May 20.

Department of Cancer Biology, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA.

IK is a mitotic factor that promotes cell cycle progression. Our previous investigation of 271 endometrial cancer (EC) samples from the Cancer Genome Atlas (TCGA) dataset showed IK somatic mutations were enriched in a cluster of patients with high-grade and high-stage cancers, and this group had longer survival. This study provides insight into how IK somatic mutations contribute to EC pathophysiology. We analyzed the somatic mutational landscape of IK gene in 547 EC patients using expanded TCGA dataset. Co-immunoprecipitation and mass spectrometry were used to identify protein interactions. In vitro and in vivo experiments were used to evaluate IK's role in EC. The patients with IK-inactivating mutations had longer survival during 10-year follow-up. Frameshift and stop-gain were common mutations and were associated with decreased IK expression. IK knockdown led to enrichment of G2/M phase cells, inactivation of DNA repair signaling mediated by heterodimerization of Ku80 and Ku70, and sensitization of EC cells to cisplatin treatment. IK/Ku80 mutations were accompanied by higher mutation rates and associated with significantly better overall survival. Inactivating mutations of IK gene and loss of IK protein expression were associated with weakened Ku80/Ku70-mediated DNA repair, increased mutation burden, and better response to chemotherapy in patients with EC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13102487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160817PMC
May 2021

Conversion of RNA Aptamer into Modified DNA Aptamers Provides for Prolonged Stability and Enhanced Antitumor Activity.

J Am Chem Soc 2021 05 14;143(20):7655-7670. Epub 2021 May 14.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.

Aptamers, synthetic single-strand oligonucleotides that are similar in function to antibodies, are promising as therapeutics because of their minimal side effects. However, the stability and bioavailability of the aptamers pose a challenge. We developed aptamers converted from RNA aptamer to modified DNA aptamers that target phospho-AXL with improved stability and bioavailability. On the basis of the comparative analysis of a library of 17 converted modified DNA aptamers, we selected aptamer candidates, GLB-G25 and GLB-A04, that exhibited the highest bioavailability, stability, and robust antitumor effect in experiments. Backbone modifications such as thiophosphate or dithiophosphate and a covalent modification of the 5'-end of the aptamer with polyethylene glycol optimized the pharmacokinetic properties, improved the stability of the aptamers by reducing nuclease hydrolysis and renal clearance, and achieved high and sustained inhibition of AXL at a very low dose. Treatment with these modified aptamers in ovarian cancer orthotopic mouse models significantly reduced tumor growth and the number of metastases. This effective silencing of the phospho-AXL target thus demonstrated that aptamer specificity and bioavailability can be improved by the chemical modification of existing aptamers for phospho-AXL. These results lay the foundation for the translation of these aptamer candidates and companion biomarkers to the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.9b10460DOI Listing
May 2021

PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway.

Int J Mol Sci 2021 Feb 13;22(4). Epub 2021 Feb 13.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2-specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22041882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918312PMC
February 2021

The hidden role of paxillin: localization to nucleus promotes tumor angiogenesis.

Oncogene 2021 01 4;40(2):384-395. Epub 2020 Nov 4.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Paxillin (PXN), a key component of the focal adhesion complex, has been associated with cancer progression, but the underlying mechanisms are poorly understood. The purpose of this study was to elucidate mechanisms by which PXN affects cancer growth and progression, which we addressed using cancer patient data, cell lines, and orthotopic mouse models. We demonstrated a previously unrecognized mechanism whereby nuclear PXN enhances angiogenesis by transcriptionally regulating SRC expression. SRC, in turn, increases PLAT expression through NF-ĸB activation; PLAT promotes angiogenesis via LRP1 in endothelial cells. PXN silencing in ovarian cancer mouse models reduced angiogenesis, tumor growth, and metastasis. These findings provide a new understanding of the role of PXN in regulating tumor angiogenesis and growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-020-01517-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275353PMC
January 2021

Aptamers: Novel Therapeutics and Potential Role in Neuro-Oncology.

Cancers (Basel) 2020 Oct 9;12(10). Epub 2020 Oct 9.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

A relatively new paradigm in cancer therapeutics is the use of cancer cell-specific aptamers, both as therapeutic agents and for targeted delivery of anticancer drugs. After the first therapeutic aptamer was described nearly 25 years ago, and the subsequent first aptamer drug approved, many efforts have been made to translate preclinical research into clinical oncology settings. Studies of aptamer-based technology have unveiled the vast potential of aptamers in therapeutic and diagnostic applications. Among pediatric solid cancers, brain tumors are the leading cause of death. Although a few aptamer-related translational studies have been performed in adult glioblastoma, the use of aptamers in pediatric neuro-oncology remains unexplored. This review will discuss the biology of aptamers, including mechanisms of targeting cell surface proteins, various modifications of aptamer structure to enhance therapeutic efficacy, the current state and challenges of aptamer use in neuro-oncology, and the potential therapeutic role of aptamers in pediatric brain tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12102889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600320PMC
October 2020

Back to the Future: Rethinking the Great Potential of lncRNA for Optimizing Chemotherapeutic Response in Ovarian Cancer.

Cancers (Basel) 2020 Aug 25;12(9). Epub 2020 Aug 25.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Ovarian cancer (OC) is one of the most fatal cancers in women worldwide. Currently, platinum- and taxane-based chemotherapy is the mainstay for the treatment of OC. Yet, the emergence of chemoresistance results in therapeutic failure and significant relapse despite a consistent rate of primary response. Emerging evidence substantiates the potential role of lncRNAs in determining the response to standard chemotherapy in OC. The objective of this narrative review is to provide an integrated, synthesized overview of the current state of knowledge regarding the role of lncRNAs in the emergence of resistance to platinum- and taxane-based chemotherapy in OC. In addition, we sought to develop conceptual frameworks for harnessing the therapeutic potential of lncRNAs in strategies aimed at enhancing the chemotherapy response of OC. Furthermore, we offered significant new perspectives and insights on the interplay between lncRNAs and the molecular circuitries implicated in chemoresistance to determine their impacts on therapeutic response. Although this review summarizes robust data concerning the involvement of lncRNAs in the emergence of acquired resistance to platinum- and taxane-based chemotherapy in OC, effective approaches for translating these lncRNAs into clinical practice warrant further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12092406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564391PMC
August 2020

Therapeutic efficacy of liposomal Grb2 antisense oligodeoxynucleotide (L-Grb2) in preclinical models of ovarian and uterine cancer.

Oncotarget 2020 Jul 21;11(29):2819-2833. Epub 2020 Jul 21.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Adaptor proteins such as growth factor receptor-bound protein-2 (Grb2) play important roles in cancer cell signaling. In the present study, we examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression (L-Grb2) in gynecologic cancer models.

Materials And Methods: Murine orthotopic models of ovarian (OVCAR5 and SKOV3ip1) and uterine (Hec1a) cancer were used to study the biological effects of L-Grb2 on tumor growth. experiments (cell viability assay, Western blot analysis, siRNA transfection, and reverse phase protein array) were carried out to elucidate the mechanisms and potential predictors of tumor response to L-Grb2.

Findings: Treatment with L-Grb2 decreased tumor growth and metastasis in orthotopic models of ovarian cancer (OVCAR5, SKOV3ip1) by reducing angiogenesis and increasing apoptosis at a dose of 15 mg/kg with no effect on mouse body weight. Treatment with L-Grb2 and paclitaxel led to the greatest decrease in tumor weight (mean ± SEM, 0.17 g ± 0.10 g) compared with that in control mice (0.99 g ± 0.35 g). We also observed a reduction in tumor burden after treatment with L-Grb2 and the anti-VEGF antibody B-20 (86% decrease in tumor weight compared with that in controls). Ovarian cancer cells with ErbB2 amplification (OVCAR8 and SKOV3ip1) were the most sensitive to Grb2 downregulation. Reverse phase protein array analysis identified significant dysregulation of metabolites (LDHA, GAPDH, and TCA intermediates) in ovarian cancer cells after Grb2 downregulation.

Interpretation: L-Grb2 has therapeutic efficacy in preclinical models of ovarian and uterine cancer. These findings support further clinical development of L-Grb2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381098PMC
July 2020

NRG1/ERBB3 Pathway Activation Induces Acquired Resistance to XPO1 Inhibitors.

Mol Cancer Ther 2020 08 4;19(8):1727-1735. Epub 2020 Jun 4.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation of the NRG1/ERBB3 pathway in SINE-resistant cells. Depletion of ERBB3 using siRNAs restored the antitumor effect of SINE and Furthermore, exogenous NRG1 decreased the antitumor effect of SINE in ovarian cancer cell lines with high ERBB3 expression, but not in those with low expression. These results suggest that NRG1 and ERBB3 expression is a potential biomarker of response to SINE treatment. The antitumor effect of SINE was reduced by exogenous NRG1 in an ERBB3-dependent manner. These findings suggest that NRG1 and ERBB3 are effective biomarkers that should be evaluated in future clinical trials and are relevant therapeutic targets for the treatment of SINE-resistant cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-19-0977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415525PMC
August 2020

Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer.

Int J Mol Sci 2020 Apr 23;21(8). Epub 2020 Apr 23.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cyclin-dependent kinase (CDK)-7 inhibitors are emerging as promising drugs for the treatment of different types of cancer that show chemotherapy resistance. Evaluation of the effects of CDK7 inhibitor, THZ1, alone and combined with tamoxifen is of paramount importance. Thus, in the current work, we assessed the effects of THZ1 and/or tamoxifen in two estrogen receptor-positive (ER+) breast cancer cell lines (MCF7) and its tamoxifen resistant counterpart (LCC2) in vitro and in xenograft mouse models of breast cancer. Furthermore, we evaluated the expression of CDK7 in clinical samples from breast cancer patients. Cell viability, apoptosis, and genes involved in cell cycle regulation and tamoxifen resistance were determined. Tumor volume and weight, proliferation marker (Ki67), angiogenic marker (CD31), and apoptotic markers were assayed. Bioinformatic data indicated CDK7 expression was associated with negative prognosis, enhanced pro-oncogenic pathways, and decreased response to tamoxifen. Treatment with THZ1 enhanced tamoxifen-induced cytotoxicity, while it inhibited genes involved in tumor progression in MCF-7 and LCC2 cells. In vivo, THZ1 boosted the effect of tamoxifen on tumor weight and tumor volume, reduced Ki67 and CD31 expression, and increased apoptotic cell death. Our findings identify CDK7 as a possible therapeutic target for breast cancer whether it is sensitive or resistant to tamoxifen therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21082974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215326PMC
April 2020

Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer.

Gut 2020 10 27;69(10):1818-1831. Epub 2020 Jan 27.

Mathematics in Medicine Program, The Houston Methodist Research Institute, Houston, Texas, USA.

Objective: To investigate the function of a novel primate-specific long non-coding RNA (lncRNA), named FLANC, based on its genomic location (co-localised with a pyknon motif), and to characterise its potential as a biomarker and therapeutic target.

Design: FLANC expression was analysed in 349 tumours from four cohorts and correlated to clinical data. In a series of multiple in vitro and in vivo models and molecular analyses, we characterised the fundamental biological roles of this lncRNA. We further explored the therapeutic potential of targeting FLANC in a mouse model of colorectal cancer (CRC) metastases.

Results: FLANC, a primate-specific lncRNA feebly expressed in normal colon cells, was significantly upregulated in cancer cells compared with normal colon samples in two independent cohorts. High levels of FLANC were associated with poor survival in two additional independent CRC patient cohorts. Both in vitro and in vivo experiments demonstrated that the modulation of FLANC expression influenced cellular growth, apoptosis, migration, angiogenesis and metastases formation ability of CRC cells. In vivo pharmacological targeting of FLANC by administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with a specific small interfering RNA, induced significant decrease in metastases, without evident tissue toxicity or pro-inflammatory effects. Mechanistically, FLANC upregulated and prolonged the half-life of phosphorylated STAT3, inducing the overexpression of VEGFA, a key regulator of angiogenesis.

Conclusions: Based on our findings, we discovered, FLANC as a novel primate-specific lncRNA that is highly upregulated in CRC cells and regulates metastases formation. Targeting primate-specific transcripts such as FLANC may represent a novel and low toxic therapeutic strategy for the treatment of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2019-318903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382985PMC
October 2020

Corrigendum to 'Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer' [EBioMedicine 38 (2018) 100-112].

EBioMedicine 2020 Feb 20;52:102630. Epub 2020 Jan 20.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1901 East Road, Unit 1950, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.102630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974767PMC
February 2020

miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer.

Cell Rep 2019 12;29(13):4389-4406.e10

Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address:

Genomic amplification of 3q26.2 locus leads to the increased expression of microRNA 551b-3p (miR551b-3p) in triple-negative breast cancer (TNBC). Our results demonstrate that miR551b-3p translocates to the nucleus with the aid of importin-8 (IPO8) and activates STAT3 transcription. As a consequence, miR551b upregulates the expression of oncostatin M receptor (OSMR) and interleukin-31 receptor-α (IL-31RA) as well as their ligands OSM and IL-31 through STAT3 transcription. We defined this set of genes induced by miR551b-3p as the "oncostatin signaling module," which provides oncogenic addictions in cancer cells. Notably, OSM is highly expressed in TNBC, and the elevated expression of OSM associates with poor outcome in estrogen-receptor-negative breast cancer patients. Conversely, targeting miR551b with anti-miR551b-3p reduced the expression of the OSM signaling module and reduced tumor growth, as well as migration and invasion of breast cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2019.11.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380555PMC
December 2019

Long non-coding RNAs in ovarian cancer: expression profile and functional spectrum.

RNA Biol 2020 11 17;17(11):1523-1534. Epub 2019 Dec 17.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.

Long non-coding RNAs (lncRNAs), initially recognized as byproducts of the transcription process, have been proven to play crucial modulatory roles in preserving overall homoeostasis of cells and tissues. Furthermore, aberrant levels of these transcripts have been shown to contribute many diseases, including cancer. Among these, many aspects of ovarian cancer biology have been found to be regulated by lncRNAs, including cancer initiation, progression and dissemination. In this review, we summarize recent studies to highlight the various roles of lncRNAs in ovary in normal and pathological conditions, immune system, diagnosis, prognosis, and therapy. We address lncRNAs that have been extensively studied in ovarian cancer and their contribution to cellular dynamics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15476286.2019.1702283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567512PMC
November 2020

A-to-I-edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosis.

J Clin Invest 2019 12;129(12):5343-5356

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Both miRNAs and A-to-I RNA editing, a widespread nucleotide modification mechanism, have recently emerged as key players in cancer pathophysiology. However, the functional impact of RNA editing of miRNAs in cancer remains largely unexplored. Here, we focused on an ADAR2-catalyzed RNA editing site within the miR-379-5p seed region. This site was under-edited in tumors relative to normal tissues, with a high editing level being correlated with better patient survival times across cancer types. We demonstrated that in contrast to wild-type miRNA, edited miR-379-5p inhibited cell proliferation and promoted apoptosis in diverse tumor contexts in vitro, which was due to the ability of edited but not wild-type miR-379-5p to target CD97. Importantly, through nanoliposomal delivery, edited miR-379-5p mimics significantly inhibited tumor growth and extended survival of mice. Our study indicates a role of RNA editing in diversifying miRNA function during cancer progression and highlights the translational potential of edited miRNAs as a new class of cancer therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI123396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877318PMC
December 2019

6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers.

Clin Cancer Res 2019 09 7;25(18):5702-5716. Epub 2019 Aug 7.

Department of Experimental Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas.

Purpose: Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 () depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of on tumor cell growth .

Results: Knockdown of inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type (wt). Silencing significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of si increased the glycolysis rate, but decreased the flow of intermediates through the pentose-phosphate pathway in cancer cells with wt, decreasing NADPH. ROS accumulated after knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma.

Conclusions: PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wt.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-3448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744996PMC
September 2019

Identifying and targeting angiogenesis-related microRNAs in ovarian cancer.

Oncogene 2019 08 9;38(33):6095-6108. Epub 2019 Jul 9.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Current anti-angiogenic therapy for cancer is based mainly on inhibition of the vascular endothelial growth factor pathway. However, due to the transient and only modest benefit from such therapy, additional approaches are needed. Deregulation of microRNAs (miRNAs) has been demonstrated to be involved in tumor angiogenesis and offers opportunities for a new therapeutic approach. However, effective miRNA-delivery systems are needed for such approaches to be successful. In this study, miRNA profiling of patient data sets, along with in vitro and in vivo experiments, revealed that miR-204-5p could promote angiogenesis in ovarian tumors through THBS1. By binding with scavenger receptor class B type 1 (SCARB1), reconstituted high-density lipoprotein-nanoparticles (rHDL-NPs) were effective in delivering miR-204-5p inhibitor (miR-204-5p-inh) to tumor sites to suppress tumor growth. These results offer a new understanding of miR-204-5p in regulating tumor angiogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-019-0862-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293105PMC
August 2019

Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease.

Cell Metab 2019 06 28;29(6):1274-1290.e9. Epub 2019 Mar 28.

Department of Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657508PMC
June 2019
-->