Epigenetic heterogeneity promotes acquired resistance to BET bromodomain inhibition in ovarian cancer

xlomafota13 shared this article with you from Inoreader Epigenetic heterogeneity promotes acquired resistance to BET bromodomain inhibition in ovarian cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3021-3038. eCollection 2021. ABSTRACT BET bromodomain inhibitors (BETi) are promising therapeutic regimens for epithelial ovarian cancer (EOC). However, early-stage clinical trials indicate that drug tolerance may limit their anti-tumor efficacy. Here, we show that JQ1-refractory EOC cells acquire reversible resistance to BET inhibition and remain dependent on BRD4 function. The insensitivity is driven by a unique non-genetic mechanism that involves clonal selection for a pre-existing cell subpopulation with ample acetylated histones and sufficient nuclear phase-separated BRD4 droplets to counteract BETi antagonism. A vertical combination approach by co-blocking BET proteins and downstream Aurora kinases proves to achieve more complete responses than single inhibitors. Collectively, our study implicates epigenetic heterogeneity in therapeutic resistance to chromatin-targeted agents and proposes a rati onal strategy to address this anticipated clinical dilemma. PMID:34249442 | PMC:PMC8263684 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Irreversible electroporation enhances immunotherapeutic effect in the off-target tumor in a murine model of orthotopic HCC

xlomafota13 shared this article with you from Inoreader Irreversible electroporation enhances immunotherapeutic effect in the off-target tumor in a murine model of orthotopic HCC Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3304-3319. eCollection 2021. ABSTRACT Irreversible electroporation (IRE) has been postulated to have an off-target effect on lesions not in the tumor-ablative field, possibly through heightened immunologic response. In this study, we evaluated whether combination IRE and immunotherapy would lead to increased tumor necrosis and T cell recruitment to both the treated tumors and tumors outside the local ablative field. An in vitro cell-IRE model was established to evaluate the ability of T lymphocytes (EL4 cell and HH cells) migration in response to Hepatocellular carcinoma (HCC) cells (Hepa1-6 and HepG2) with IRE treatment. An orthotopic HCC mouse model was established by implantation of 1mm^3 sections of Hepa1-6 tumor tissues into the right and left lobes of the liver. The Hepa1-6 cells and HepG2 cells with IRE treatment increased the migration ability of EL4 cell and HH cells, specifically when they were pretreated with immunotherapeutic agents in vitro. In the orthotopic HCC mouse model, IRE+immunotherapy treatment enhanced the necrosis and subpopulation of infiltrated CD8 positive cells, but attenuated the tumor associated inflammatory cells in both IRE target tumor tissues and IRE off-target tumor tissues from the mice with 4 weeks of immunotherapy following IRE. This study provided the evidence that combination of IRE and immunotherapy enhances tumor necrosis and immune responses, not only in the IRE-treated tumor but also in the off-target tumor. PMID:34249464 | PMC:PMC8263666 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Hypoxia-induced lncRNA CASC9 enhances glycolysis and the epithelial-mesenchymal transition of pancreatic cancer by a positive feedback loop with AKT/HIF-1alpha signaling [Retraction]

xlomafota13 shared this article with you from Inoreader Hypoxia-induced lncRNA CASC9 enhances glycolysis and the epithelial-mesenchymal transition of pancreatic cancer by a positive feedback loop with AKT/HIF-1alpha signaling [Retraction] Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3377. eCollection 2021. ABSTRACT [This retracts the article on p. 123 in vol. 11, PMID: 33520364.]. PMID:34249470 | PMC:PMC8263686 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Low expression of miR-195 is associated with cell proliferation, glycolysis and poor survival in estrogen receptor (ER)-positive but not in triple negative breast cancer

xlomafota13 shared this article with you from Inoreader Low expression of miR-195 is associated with cell proliferation, glycolysis and poor survival in estrogen receptor (ER)-positive but not in triple negative breast cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3320-3334. eCollection 2021. ABSTRACT MiR-195 is a tumor suppressive microRNA in breast cancer. Its clinical relevance remains debatable as it has only been studied via in vitro experiments or small cohort studies. We analyzed a total of 2,038 patients in the TCGA and METABRIC cohorts to assess whether low miR-195 expressing tumors are associated with aggressive cancer characteristics and poor prognostic outcomes. The median cutoff of miR-195 expression was used to split the groups into miR-195 high and low groups. Low miR-19 expressing tumors demonstrated high cell proliferating features by enriching the gene sets associated with cell proliferation, MKI67 expression and pathological grade. One-third of the top target miR-195 genes were related to cell proliferation. Low miR-195 expressing tumors were associated with both pro-cancerous and anti-cancerous immune cells. Low miR-195 expressing tumors wer e associated with enhanced glycolysis and poor survival in ER-positive tumors, but not other subtypes of breast cancer. In conclusion, low expression of miR-195 in ER-positive breast cancer was associated with enhanced cancer cell proliferation, glycolysis, and worse overall survival. PMID:34249465 | PMC:PMC8263660 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

OX40 agonist combined with irreversible electroporation synergistically eradicates established tumors and drives systemic antitumor immune response in a syngeneic pancreatic cancer model

xlomafota13 shared this article with you from Inoreader OX40 agonist combined with irreversible electroporation synergistically eradicates established tumors and drives systemic antitumor immune response in a syngeneic pancreatic cancer model Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2782-2801. eCollection 2021. ABSTRACT In this study, we intended to explore a novel combination treatment scheme for pancreatic cancer, using irreversible electroporation (IRE) and OX40 agonist. We further aimed to investigate the capacity and mechanism of this combination treatment using an in vivo mouse aggressive pancreatic cancer model. To this end, mice subcutaneously injected with KPC1199 pancreatic tumor cells were treated with IRE, followed by intraperitoneal injection of OX40 agonist. Tumor growth and animal survival were observed. Flow cytometry analysis, immunohistochemistry, and immunofluorescence were used to evaluate the immune cell populations within the tumors. The tumor-specific immunity was assessed using ELISpot assay. Besides, the cytokine patterns both in serum and tumors were identified using Luminex assay. After combination therapy with IRE and OX40 agonist, 80% of the mi ce completely eradicated the established subcutaneous tumors, during the 120 days observation period. Rechallenging these tumor-free mice at day 120 with KPC1199 tumor cells leads to complete resistance to tumor growth, suggesting that the combination therapy generated long-term-specific antitumor immune memory. Moreover, combination therapy significantly delayed the growth of contralateral untreated tumors, and significantly prolonged animal survival, suggesting that a potent systematic anti-tumor immunity was induced by combination therapy. Mechanically, combination therapy amplified antitumor immune response induced by IRE, as manifested by the increased quality and quantity of CD8+ T cells trigged by IRE. Together, these results provide strong evidence for the clinical assessment of the combination of IRE and OX40 agonist in patients with pancreatic cancer. PMID:34249428 | PMC:PMC8263674 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

SERMs suppresses the growth of ERalpha positive cervical cancer xenografts through predominant inhibition of extra-nuclear ERalpha expression

xlomafota13 shared this article with you from Inoreader SERMs suppresses the growth of ERalpha positive cervical cancer xenografts through predominant inhibition of extra-nuclear ERalpha expression Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3335-3353. eCollection 2021. ABSTRACT The role of estrogens and estrogen receptors (ER) in cervical cancer (CC) is not well established. However, epidemiological studies and abundant evidence from genetically engineered mouse models support such hypothesis. In this study, we have addressed estrogen responsiveness in a human CC cell line xenograft mouse model. We assessed the sensitivity of Ethynyl Estradiol (EE), SERMs (fulvestrant, MPP) and a non-SERM (EGCG) to competitively modulate the growth of ERα+ve MS751 CC xenografts. We also checked the agonistic-antagonistic propensity of the above treatments to alter the histology of ovariectomised mouse uterine cervix. Chronic EE treatment encouraged the growth of ERα+ve MS751 CC xenografts, while SERMs and EGCG significantly decreased tumor formation. SERMs were found to inhibit ERα expression, localized within cytoplasmic and mem brane compartments. Conversely, ERα was not inducible and EE administration suppressed the growth of ERα-ve HeLa CC xenografts. SERMs competitively induced atrophic features to uterine cervix, with MPP giving rise to mucinous metaplasia in the ectocervix. We have demonstrated that, estrogen sensitivity mediated through ERα has promoted CC tumorigenesis. This in turn was modulated by SERMs, predominantly through inhibition of extra-nuclear ERα expression. Though, induction of hyper-estrogenic status in the ectocervix, might underrate the utility of SERMs in ERα+ve CC. PMID:34249466 | PMC:PMC8263693 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

HP1BP3 promotes tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal squamous cell carcinoma

xlomafota13 shared this article with you from Inoreader HP1BP3 promotes tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal squamous cell carcinoma Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2928-2943. eCollection 2021. ABSTRACT HP1BP3, an ubiquitously expressed nuclear protein belonging to the H1 histone family of proteins, plays an important role in cell growth and viability. Recently, it was reported that HP1BP3 exclusively regulates miRNA biogenesis by enhancing transcriptional miRNA processing. Although HP1BP3 has previously been implicated in common cancer types, the mechanistic functions and effects of HP1BP3 and its role in the prognosis of esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we report that ESCC tissues and cell lines show increased endogenous expression of HP1BP3. Knockdown of HP1BP3 in TE-1 cells significantly inhibited tumor growth and metastasis in vivo emphasizing its role in cell proliferation and invasion. In contrast, overexpression of HP1BP3 significantly enhanced tumor growth and metastasis in Eca-109 cells. Further, we found that HP1BP 3 regulates these functions by upregulating miR-23a, which directly binds to the 3'UTR region of TRAF5 downstream to alter cell survival and proliferation. Our findings describe a role for HP1BP3 in promoting tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal cancer. This study provides novel insights into the potential of targeting miRNAs for therapy and as clinical markers for cancer progression. PMID:34249436 | PMC:PMC8263663 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.