Biology subjects

Rader, J. S.

Publications and source records attributed to Rader, J. S..

5 recordsLinked to original sources

bioRxiv2026

TAOK3 inhibition constrains invasion, potentiates paclitaxel, and reprograms the tumor microenvironment toward anti-tumor immunity in cervical cancer

TAOK3 is a lesser-studied MAPK family serine/threonine kinase our group has shown to be targeted by HPV integration, suggesting a potential role in driving invasive cervical cancer (ICC). Here, we profiled TAOK3 expression in patient tumors, metastases, and cervical cancer models and localized TAOK3 within a tumor epithelial subpopulation by integrating two single-cell RNA-seq datasets. Functional consequences of TAOK3 loss were assessed with siRNA and CRISPRi in cell lines and 3D spheroids. In vivo effects were evaluated in intracervical xenografts with species-specific RNA-seq to resolve tumor versus microenvironmental responses. TAOK3 mRNA/protein were elevated in primary and metastatic ICC and primarily localized to a keratin-positive epithelial subset (T3epi) enriched for cadherin/S100 binding, vesicle/endocytic pathways, and leading-edge programs. TAOK3 silencing reprogrammed transcriptomes and proteomes toward reduced WNT/cell-cycle and motility signaling, altered endocytosis and cytoskeleton organization, and reshaped phospho-networks linked to chromatin remodeling and ERBB2-ERBB3/cytoskeletal kinase activity. Functionally, TAOK3 inhibition prolonged G2/M, suppressed invasion, and enhanced sensitivity to low dose paclitaxel. Prolonged inactivation induced methuosis-like cell death with extracellular ATP release. In xenografts, TAOK3 knockdown reduced tumor burden, downregulated KRT14--a leader cell marker--within the human tumor compartment, and enriched microenvironmental pathways for immune activation, with a specific decrease in CD206+ M2 macrophages. TAOK3 delineates an invasion-competent epithelial state in ICC and coordinates cell-cycle control, cytoskeleton-membrane dynamics, and tumor-immune crosstalk. Genetic or pharmacologic TAOK3 inhibition constrains tumor growth, potentiates paclitaxel, and remodels the microenvironment toward anti-tumor immunity, supporting TAOK3 as a potential therapeutic target and biomarker in ICC. Statement of SignificanceTAOK3 marks an invasion-competent epithelial subpopulation in cervical cancer. TAOK3 inhibition slows tumor growth, enhances chemoresponse, and reduces M2 macrophages, revealing TAOK3 as a potential therapeutic target and biomarker for patient stratification.

cancer biology↗

bioRxiv2026

MRPL47 as a Novel Mitochondrial Biomarker for Early Detection and Therapeutic Response in Ovarian Cancer

MRPL47 (Mitochondrial Ribosomal Protein Large Subunit 47) gene in chromosome 3q26 encodes a protein that is part of the large subunit of the mitochondrial ribosome. We observed that MRPL47 is frequently amplified and overexpressed in ovarian cancer samples. Importantly, increased expression of MRPL47 mRNA is associated with high levels of MRPL47 protein in ovarian cancer patients. High expression of MRPL47 is also associated with poor overall and recurrence free survival of ovarian cancer patients. Notably, MRPL47 improved metabolic fitness by enhancing cellular respiration, and glycolysis in cancer cells. Gene set enrichment analysis and target specific knockdown assays revealed that MYC transcription factor regulates MRPL47 expression. Furthermore, MRPL47 was identified very high in the plasma samples of ovarian cancer patients compared to those of healthy volunteers. MRPL47 was also associated with cisplatin resistance, whereas its expression predicted sensitivity to cisplatin therapy. Taken together, we demonstrated that MRPL47 can be used as a diagnostic biomarker for ovarian cancer and other cancers with 3q26 chromosomal amplification.

cancer biology↗

bioRxiv2023

Orphan nuclear receptor NR2E3 and its small-molecule agonist induce cancer cell apoptosis through regulating p53, IFNα and MYC pathways

Orphan nuclear receptor NR2E3 activates p53 and induces cancer cell apoptosis. Further studies on p53-dependent and -independent functions of wild-type and mutated NR2E3 are needed. Herein, we showed that NR2E3 enhanced p53-DNA interactions in diverse cancer cells and up-regulated p53 and IFN pathways while down-regulating MYC pathway in cervical cancer cells. Studies of "All of Us" and TCGA databases showed NR2E3 nonsynonymous mutations associating with four cancers. We stratified NR2E3 SNVs for their cancer implications with the p53 reporter. A cancer-associated NR2E3R97Hmutation not only lost the wild-types tumor-suppressing functions but also prohibited the wild-type from enhancing p53 acetylation. These observations implicated the potential for pharmaceutically activating NR2E3 to suppress cancer. Indeed, NR2E3s small-molecule agonist 11a repressed 2-D and 3-D cultures of primary cells and cell lines of cervical cancer, in which screening FDA-approved anti-cancer drugs identified HDAC-1/2 inhibitor Romidepsin operating synergistically with 11a. The underlying molecular mechanisms included 11as down-regulating the transcription of Multidrug Resistance Protein ABCB1 that Romidepsin up-regulated. Transcriptomics studies revealed three synergy modes: (1) "sum-up" mode that the p53 pathway activated individually by 11a and Romidepsin got stronger by the combo; (2) "antagonism" mode that Romidepsin counteracted the activation of the Kras pathway by 11a; and (3) "de novo" mode that the combo instead of each individual drug repressed the MYC pathway. Conclusively, our experiments provide new data supporting tumor-suppressor like functions for wild-type NR2E3, reveal roles of mutated NR2E3 in cancer, and address values of NR2E3s agonist 11a in cancer therapy alone and combined.

cancer biology↗

bioRxiv2023

Genomic structures and regulation patterns at HPV integration sites in cervical cancer

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

genomics↗

bioRxiv2020

RNA-binding protein FXR1 drives cMYC translation by mRNA circularization through eIF4F recruitment in ovarian cancer

BackgroundThe RNA-binding protein FXR1 (fragile X-related protein 1) has been implicated as an important regulator of post-transcriptional changes of mRNAs. However, its role in mRNA circularization and recruitment of eukaryotic translation initiation factors for protein translation remains obscure. Here, we aimed to investigate the molecular mechanisms and potential clinical applications of FXR1 in ovarian cancer growth and progression. MethodsFXR1 copy number variation, mRNA expression, protein levels, and their association with prognosis were determined in clinical datasets. An orthotopic ovarian cancer model and bioluminescence imaging were used for preclinical evaluation of FXR1 in vivo. Reverse phase protein arrays (RPPA) and qPCR arrays were performed to identify FXR1s key targets and downstream effects. SUnSET and polysome profiling were used to determine the translational effects of FXR1. Immunoprecipitation and immunofluorescence were performed to identify the interaction between FXR1 and cMYC mRNA and eIF4F complex. RNA-immunoprecipitation (RIP), RNA electrophoretic mobility shift assays (REMSA), proximity ligation assays (PLA), and biochemical assays were used to identify the specific site on cMYC mRNA to which FXR1 binds to promote mRNA circularization and translation. ResultsWe found that amplification and copy-gain of FXR1 increased the expression of FXR1 mRNA and FXR1 protein in ovarian cancer patients, and these events associated with poor prognosis. We demonstrated that FXR1 binds to AU-rich elements (ARE) within the 3 untranslated region (3UTR) of cMYC. As a consequence, FXR1 binding to cMYC 3UTR leads to the circularization of mRNA and facilitated the recruitment of eukaryotic translation initiation factors (eIFs) to translation start site for improving protein synthesis. ConclusionWe found that FXR1 upregulates a known oncogene, cMYC, by binding to AU-rich elements within the 3UTR, leading to the recruitment of the eIF4F complex for cMYC translation. Our findings uncover a novel mechanism of action of FXR1 in tumorigenesis and provides opportunities to use FXR1 and its downstream effectors as biomarkers or therapeutic targets in ovarian and other cancers.

cancer biology↗