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.

DLX5 promotes osteosarcoma progression via activation of the NOTCH signaling pathway

xlomafota13 shared this article with you from Inoreader DLX5 promotes osteosarcoma progression via activation of the NOTCH signaling pathway Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3354-3374. eCollection 2021. ABSTRACT The distal-less (dlx) homeobox transcription factors have been implicated roles in bone development. DLX5, in particular, was shown to play essential roles in osteoblast differentiation by targeting RUNX2, a master transcription factor for bone development. Interestingly, DLX5 has also been shown to play an oncogenic role in lung and other cancers, possibly via regulation of MYC expression. Given its dual roles in bone and cancer, this study aimed to investigate the effect of DLX5 on progression of osteosarcoma (OS), the primary bone cancer that is characterized by abnormal bone formation and osteoblast activity. Expression of DLX5 in OS cell lines was detected by quantitative real-time PCR (qRT-PCR) and western blot (WB). In vitro and in vivo assays were performed to investigate the oncogenic function of DLX5 in OS cells and xenograft models. Luciferase reporter assay was performed to determine the underlying mechanism of DLX5-mediated OS aggressiveness. The results showed that DLX5 was differentially expressed in OS cell lines, with significantly upregulated levels in HOS and MG-63 and relatively low levels in U2OS and 143B cell lines, compared with the normal bone cell line. DLX5 knockdown in HOS and MG-63 cell lines by siRNA inhibited OS cell growth and progression, and induced cell apoptosis and cell cycle changes both in vitro and in vivo. Meanwhile, DLX5 overexpression had the opposite effect on U2OS and 143B cell lines. Notably, a positive correlation between the expression patterns of NOTCH1 and DLX5 was also observed. The expression levels of NICD (NOTCH1 intracellular domain) and HES1 (classical target of NOTCH) were closely associated with DLX5 expression. Whereas knockdown of DLX5 in OS cells resulted in decreased expression of NOTCH1 and reduced cell proliferation and migration, which were rescued by overexpression of NOTCH1. W e further analyzed DLX5 and NOTCH1 genes using JASPAR software and found two potential DLX5 binding sites within the NOTCH1 promoter. Dual-luciferase assay demonstrated that DLX5 specifically activates the NOTCH1 promoter and controls its expression. Taken together, our results support that DLX5 plays an oncogenic role in OS development, which can at least partially, be attributed to activation of the NOTCH signaling pathway. PMID:34249467 | PMC:PMC8263696 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Predicting early recurrence for resected pancreatic ductal adenocarcinoma: a multicenter retrospective study in China

xlomafota13 shared this article with you from Inoreader Predicting early recurrence for resected pancreatic ductal adenocarcinoma: a multicenter retrospective study in China Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3055-3069. eCollection 2021. ABSTRACT A precise classification of early recurrence (ER) after radical surgery of pancreatic ductal adenocarcinoma (PDAC) has not been standardized. We aim to develop an optimal cut-off based on scientific evidence to distinguish early and late recurrence (LR) for PDAC after radical surgery and develop a predictive model for ER of PDAC. The best threshold for recurrence-free survival (RFS) was assessed with a minimum P-value method, and patients were categorized into ER and LR groups. We used a logistic regression model to assess potential risk factors for ER and develop a predictive model for ER risk. The best threshold between high-risk and intermediate-high-risk groups was identified by using the receiver operating characteristic curve. Among 3,279 patients included, 1,234 (37.6%) experienced ER. The RFS of 9 months is the optimal threshold to distinguish ER an d LR. Univariable and multivariable analysis identified four preoperative risk factors for ER, including larger tumor maximal diameter on computed tomography (CT), enlarged lymph nodes on CT, carbohydrate antigen (CA) 125 > 35 U/ml, and CA19-9 > 235 U/ml. The concordance index (C-index) for the predictive model in the training cohort and the validation cohort was 0.651 (95% confidence interval (CI): 0.624-0.678), and 0.636 (95% CI: 0.593-0.679), respectively, showing promising predictive ability. The high-risk group had a score above 203, and the corresponding risk of ER for this group was 56.7%. An RFS of 9 months is the best threshold to distinguish ER and LR. The model can accurately predict the risk of ER in PDAC after radical resection, and risk grouping can predict the patients who could benefit from upfront surgery. PMID:34249444 | PMC:PMC8263647 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

MicroRNA-613 suppresses proliferation, migration and invasion of osteosarcoma by targeting c-MET [Retraction]

xlomafota13 shared this article with you from Inoreader MicroRNA-613 suppresses proliferation, migration and invasion of osteosarcoma by targeting c-MET [Retraction] Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3375. eCollection 2021. ABSTRACT [This retracts the article on p. 2869 in vol. 6, PMID: 28042506.]. PMID:34249468 | PMC:PMC8263675 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

A heptamethine cyanine dye serves as a potential marker for myeloid-derived suppressor cells

xlomafota13 shared this article with you from Inoreader A heptamethine cyanine dye serves as a potential marker for myeloid-derived suppressor cells Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2853-2866. eCollection 2021. ABSTRACT Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with inhibitory effects on T cell-mediated immune response. MDSCs accumulate under many pathological conditions, including cancers, to avoid anticancer immunity. Unlike mouse MDSCs, common specific surface markers for human MDSCs are not clearly defined, mainly due to the complexity of MDSC subsets. In this study, we investigate specific responses of the infrared dye MHI-148 to MDSCs. Mice bearing 4T1 breast cancer cells were established, and splenocytes were isolated. Flow cytometric analyses demonstrated that MHI-148 was reactive to over 80% of MDSC-specific cells manifesting CD11b+/Gr-1+ acquired from both tumor-bearing mice and naive mice. Cells sorted positive for either CD11b/Gr-1 or MHI-148 were also identical to their counterparts (99.7% and 97.7%, respectively). MHI-148, however, was not reactive to lymphocyte or monocyte populations. To determine whether MHI-148-reactive cells exert inhibitory effects on T cell proliferation, an EdU-based T cell assay was performed. MHI-148 reactive cells significantly reduced T cell proliferation with increased arginase activity and nitrite production. In an attempt to test MHI-148 as a marker for human MDSCs, MHI-148 was specifically reactive to CD11b+/CD33+/CD14- granulocytic MDSCs acquired from selected cancer patients. This study demonstrates that the near-infrared dye MHI-148 specifically reacts to mouse splenocytes with known MDSC-specific markers that have T cell suppressive functions. The dye also selectively binds to a subpopulation of immature myeloid cells acquired from cancer patients. While it is not clear how MHI-148 specifically stains MDSCs, this dye can be a novel tool to detect MDSCs and to predict the prognosis of human cancer p atients. PMID:34249432 | PMC:PMC8263665 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.