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1.
Proc Natl Acad Sci U S A ; 120(23): e2122053120, 2023 06 06.
Article in English | MEDLINE | ID: mdl-37252969

ABSTRACT

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17ß-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17ß-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, we observed increased levels of let-7a-5p and let-7d-5p in EVs derived from the blood of premenopausal ER+ BC patients, and elevated EV levels in patients with high BMI, both conditions associated with higher levels of 17ß-estradiol. In brief, we identified a unique estrogen-driven mechanism by which ER+ BC cells eliminate tumor suppressor miRNAs in EVs, with effects on modulating tumor-associated macrophages in the microenvironment.


Subject(s)
Breast Neoplasms , Extracellular Vesicles , MicroRNAs , Humans , Female , MicroRNAs/genetics , MicroRNAs/metabolism , Breast Neoplasms/pathology , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Estradiol/pharmacology , Estradiol/metabolism , Estrogens/metabolism , Extracellular Vesicles/genetics , Extracellular Vesicles/metabolism , Tumor Microenvironment
2.
J Immunother Cancer ; 10(10)2022 10.
Article in English | MEDLINE | ID: mdl-36283735

ABSTRACT

Downregulation of MHC class I (MHCI) molecules on tumor cells is recognized as a resistance mechanism of cancer immunotherapy. Given that MHCI molecules are potent regulators of immune responses, we postulated that the expression of MHCI by tumor cells influences systemic immune responses. Accordingly, mice-bearing MHCI-deficient tumor cells showed reduced tumor-associated extramedullary myelopoiesis in the spleen. Depletion of natural killer (NK) cells abrogated these differences, suggesting an integral role of immune-regulatory NK cells during tumor progression. Cytokine-profiling revealed an upregulation of TNF-α by NK cells in tumors and spleen in mice-bearing MHCI expressing tumors, and inhibition of TNF-α enhanced host myelopoiesis in mice receiving adoptive transfer of tumor-experienced NK cells. Our study highlights a critical role of NK cells beyond its identity as a killer lymphocyte and more importantly, the potential host responses to a localized tumor as determined by its MHCI expression.


Subject(s)
Myelopoiesis , Neoplasms , Mice , Animals , Tumor Necrosis Factor-alpha , Killer Cells, Natural , Histocompatibility Antigens Class I
3.
Gastroenterology ; 159(6): 2146-2162.e33, 2020 12.
Article in English | MEDLINE | ID: mdl-32805281

ABSTRACT

BACKGROUND & AIMS: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic. METHODS: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2'-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients. RESULTS: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients. CONCLUSIONS: We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.


Subject(s)
Chromosomal Instability , Colorectal Neoplasms/genetics , Neoplasms, Experimental/genetics , RNA, Long Noncoding/metabolism , RNA-Binding Proteins/genetics , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aurora Kinase B/metabolism , Azoxymethane/toxicity , Carcinogenesis/genetics , Cell Line, Tumor , Colon/cytology , Colon/pathology , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/pathology , Cytogenetic Analysis , Dextrans/toxicity , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Intestinal Mucosa/cytology , Intestinal Mucosa/pathology , Male , Mice , Mice, Transgenic , Neoplasms, Experimental/chemically induced , Neoplasms, Experimental/pathology , Organoids , Primary Cell Culture , Proto-Oncogene Proteins c-myc/metabolism , RNA, Long Noncoding/genetics , RNA-Binding Proteins/metabolism , Signal Transduction/genetics
4.
Cancer Drug Resist ; 2: 1178-1192, 2019 Dec 19.
Article in English | MEDLINE | ID: mdl-31867576

ABSTRACT

One of the major challenges in oncology is drug resistance, which triggers relapse and shortens patients' survival. In order to promote drug desensitization, cancer cells require the establishment of an ideal tumor microenvironment that accomplishes specific conditions. To achieve this objective, cellular communication is a key factor. Classically, cells were believed to restrictively communicate by ligand-receptor binding, physical cell-to-cell interactions and synapses. Nevertheless, the crosstalk between tumor cells and stroma cells has also been recently reported to be mediated through exosomes, the smallest extracellular vesicles, which transport a plethora of functionally active molecules, such as: proteins, lipids, messenger RNA, DNA, microRNA or long non-coding RNA (lncRNAs). LncRNAs are RNA molecules greater than 200 base pairs that are deregulated in cancer and other diseases. Exosomal lncRNAs are highly stable and can be found in several body fluids, being considered potential biomarkers for tumor liquid biopsy. Exosomal lncRNAs promote angiogenesis, cell proliferation and drug resistance. The role of exosomal lncRNAs in drug resistance affects the main treatment strategies in oncology: chemotherapy, targeted therapy, hormone therapy and immunotherapy. Overall, knowing the molecular mechanisms by which exosomal lncRNA induce pharmacologic resistance could improve further drug development and identify drug resistance biomarkers.

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