Epithelial ovarian cancer (EOC), a leading cause of gynecological cancer-related morbidity and mortality and the most common type of ovarian cancer (OC), is widely characterized by alterations in the Epidermal Growth Factor (EGF) signaling pathways. The phenomenon of metastasis is largely held accountable for the majority of EOC-associated deaths. Existing literature reports substantiate evidence on the indispensable role of metabolic reprogramming, particularly the phenomenon of the \'Warburg effect\' or aerobic glycolysis in priming the cancer cells towards Epithelial to Mesenchymal transition (EMT), subsequently facilitating EMT. Considering the diverse roles of growth factor signaling across different stages of oncogenesis, our prime emphasis was laid on unraveling mechanistic details of EGF-induced \'Warburg effect\' and resultant metastasis in EOC cells. Our study puts forth Ets1, an established oncoprotein and key player in OC progression, as the prime metabolic sensor to EGF-induced cues from the tumor microenvironment (TME). EGF treatment has been found to induce Ets1 expression in OC cells predominantly through the Extracellular Signal-Regulated Kinase1/2 (ERK1/2) pathway activation. This subsequently results in pronounced glycolysis, characterized by an enhanced lactate production through transcriptional up-regulation of key determinant genes of the central carbon metabolism namely, hexokinase 2 (HK2) and monocarboxylate transporter 4 (MCT4). Furthermore, this study reports an unforeseen combinatorial blockage of HK2 and MCT4 as an effective approach to mitigate cellular metastasis in OC. Collectively, our work proposes a novel mechanistic insight into EGF-induced glycolytic bias in OC cells and also sheds light on an effective therapeutic intervention approach exploiting these insights.

Breast cancer ranks as the most prevalent cancer globally, surpassing lung cancer, with recurrence/metastasis to be its main account for the cancer-related mortality. MicroRNAs (miRNAs) participate critically in various physiological and pathological processes through posttranscriptional regulation of downstream genes. Our preliminary findings identified miR-338-5p, potentially linked to metastasis in breast cancer, a previously unexplored area. Analysis of the GSE38867 dataset revealed the decreased miR-338-5p expression in metastatic breast cancer compared to normal tissues. Cellular function experiments and a xenograft tumor model demonstrated the inhibitory function of miR-338-5p on the progression of breast cancer in vitro and in vivo. Furthermore, it downregulated the expression of mesenchymal biomarkers and NOTCH1 significantly. With the predicting targets of miR-338-5p and transcription factors of the NOTCH1 gene, coupled with dual luciferase reporter assays, it is identified ETS1 as the interactor between miR-338-5p and NOTCH1. In breast cancer tissues, as well as in our xenograft tumor model, expression of ETS1 and NOTCH1 was positively correlated using immunohistochemical staining. This study reports, for the first time, on the miR-338-5p/ETS1/NOTCH1 axis and its pivotal role in breast cancer proliferation and metastasis. These findings propose a novel therapeutic strategy for breast cancer patients and lays a foundation for its clinical detection and treatment evaluation.

BACKGROUND: Circular RNAs (circRNAs), produced by reverse splicing, act as important players in human cancers. We aimed to assess the biological functions of circRNA pituitary homeobox 1 (circ-PITX1) in non-small-cell lung cancer (NSCLC).
METHODS: qRT-PCR was employed to determine RNA expression. Biological behaviors of NSCLC cells were assessed by CCK-8, colony formation, EdU assay, flow cytometry, wound healing, and transwell assays. Glutamine catabolism was examined via the measurement of glutamine consumption, α-ketoglutarate levels, as well as ATP levels. Protein levels were detected by western blot assays. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to reveal the mechanism responsible for circ-PITX1 regulating NSCLC cell malignancy. The murine xenograft model was established to investigate circ-PITX1\'s effect on tumor formation.
RESULTS: Circ-PITX1 was overexpressed in NSCLC tissue samples and cells. Its low expression repressed NSCLC cell proliferation and motility. Moreover, our data revealed its downregulation inhibited glutamine catabolism and tumor formation and promoted cell apoptosis. In addition, circ-PITX1 bound to miR-615-5p, and its inhibitory effect on tumor cellular behaviors could be reversed after decreasing miR-615-5p expression. The miRNA targeted E26 transformation specific-1 (ETS1), whose upregulation abolished miR-615-5p overexpression-induced effects in NSCLC cells. Furthermore, circ-PITX1 positively modulated ETS1 production through interaction with miR-615-5p.
CONCLUSIONS: Circ-PITX1 facilitated NSCLC progression via modulating miR-615-5p/ETS1 pathway.

Prostate cancer remains the most prevalent malignancy diagnosed in men worldwide. Epithelial cell transforming sequence 2 (ECT2) is an oncogene involved in the progression of human tumors. The present study aimed to explore the involvement of ECT2 in prostate cancer and its participation in the malignant progression of prostate cancer. ECT2 expression in prostate cancer cell lines was examined via reverse transcription-quantitative PCR and western blotting. The effects of knockdown of ECT2 expression in PC-3 cells on cellular biological behaviors, including proliferation, migration and invasion, were examined using Cell Counting Kit-8, colony formation, wound healing and Transwell assays. The glycolysis level was determined based on the lactate release, glucose uptake, oxygen consumption rate and extracellular acidification rate. The binding relationship between ECT2 and ETS1 was verified using luciferase reporter and chromatin immunoprecipitation assays. The results indicated that ECT2 was highly expressed in prostate cancer cell lines. Knockdown of ECT2 expression could inhibit cell proliferation, migration, invasion and glycolysis. In addition, the transcription factor ETS1 could directly bind to the ECT2 promoter and positively regulate ECT2 expression. These data were combined with the results of rescue experiments and demonstrated that the inhibitory effects of the knockdown of ECT2 expression on the malignant behavior and glycolysis of prostate cancer cells were partially reversed by ETS1 overexpression. In conclusion, ETS1 induced transcriptional upregulation of ECT2 and enhanced the malignant biological behaviors of prostate cancer cells, thereby promoting the progression of prostate cancer. This evidence provides a theoretical basis for the treatment of prostate cancer.

Drug resistance after long-term use of Tyrosine kinase inhibitors (TKIs) has become an obstacle for prolonging the survival time of patients with clear cell renal cell carcinoma (ccRCC). Here, genome-wide CRISPR-based screening to reveal that HDAC8 is involved in decreasing the sensitivity of ccRCC cells to sunitinib is applied. Mechanically, HDAC8 deacetylated ETS1 at the K245 site to promote the interaction between ETS1 and HIF-2α and enhance the transcriptional activity of the ETS1/HIF-2α complex. However, the antitumor effect of inhibiting HDAC8 on sensitized TKI is not very satisfactory. Subsequently, inhibition of HDAC8 increased the expression of NEK1, and up-regulated NEK1 phosphorylated ETS1 at the T241 site to promote the interaction between ETS1 and HIF-2α by impeded acetylation at ETS1-K245 site is showed. Moreover, TKI treatment increased the expression of HDAC8 by inhibiting STAT3 phosphorylation in ccRCC cells is also found. These 2 findings highlight a potential mechanism of acquired resistance to TKIs and HDAC8 inhibitors in ccRCC. Finally, HDAC8-in-PROTACs to optimize the effects of HDAC8 inhibitors through degrading HDAC8 and overcoming the resistance of ccRCC to TKIs are synthesized. Collectively, the results revealed HDAC8 as a potential therapeutic candidate for resistance to ccRCC-targeted therapies.

ETS proto-oncogene 1 (ETS1) is a transcription factor (TF) critically involved in lymphoid cell development and function. ETS1 expression is tightly regulated throughout differentiation and activation in T-cells, natural killer (NK) cells, and B-cells. It has also been described as an oncogene in a range of solid and hematologic cancer types. Among hematologic malignancies, its role has been best studied in T-cell acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia/lymphoma (ATLL), and diffuse large B-cell lymphoma (DLBCL). Aberrant expression of ETS1 in these malignancies is driven primarily by chromosomal amplification and enhancer-driven transcriptional regulation, promoting the ETS1 transcriptional program. ETS1 also facilitates aberrantly expressed or activated transcriptional complexes to drive oncogenic pathways. Collectively, ETS1 functions to regulate cell growth, differentiation, signaling, response to stimuli, and viral interactions in these malignancies. A tumor suppressor role has also been indicated for ETS1 in select lymphoma types, emphasizing the importance of cellular context in ETS1 function. Research is ongoing to further characterize the clinical implications of ETS1 dysregulation in hematologic malignancies, to further resolve binding complexes and transcriptional targets, and to identify effective therapeutic targeting approaches.

Angiogenesis serves as the determinate element of pulp regeneration. Dental pulp stem cell (DPSC) implantation can promote the regeneration of dental pulp tissue. Herein, the role of m6A methyltransferase methyltransferase-like 3 (METTL3) in regulating DPSCs-induced angiogenesis during pulp regeneration therapy was investigated. Cell DPSC viability, HUVEC migration, and angiogenesis ability were analyzed by CCK-8 assay, wound healing, Transwell assay, and tube formation assay. The global and EST1 mRNA m6A levels were detected by m6A dot blot and Me-RIP. The interactions between E26 transformation-specific proto-oncogene 1(ETS1), human antigen R(HuR), and METTL3 were analyzed by RIP assay. The relationship between METTL3 and the m6A site of ETS1 was performed by dual-luciferase reporter assay. ETS1 mRNA stability was examined with actinomycin D. Herein, our results revealed that human immature DPSCs (hIDPSCs) showed stronger ability to induce angiogenesis than human mature DPSCs (hMDPSCs), which might be related to ETS1 upregulation. ETS1 knockdown inhibited DPSCs-induced angiogenesis. Our mechanistic experiments demonstrated that METTL3 increased ETS1 mRNA stability and expression level on DPSCs in an m6A-HuR-dependent manner. ETS1 upregulation abolished sh-METTL3\'s inhibition on DPSCs-induced angiogenesis. METTL3 upregulation promoted DPSCs-induced angiogenesis by enhancing ETS1 mRNA stability in an m6A-HuR-dependent manner. This study reveals a new mechanism by which m6A methylation regulates angiogenesis in DPSCs, providing new insights for stem cell-based tissue engineering.

A microRNA miR-200c-3p is a regulator of epithelial-mesenchymal transition to control adhesion and migration of epithelial and mesenchymal cells. However, little is known about whether miR-200c-3p affects lymphocyte adhesion and migration mediated by integrins. Using TK-1 (a T lymphoblast cell) as a model of T cell, here we show that repressed expression of miR-200c-3p upregulated α4 integrin-mediated adhesion to and migration across mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Conversely, overexpression of miR-200c-3p downregulated α4 integrin-mediated adhesion and migration. Unlike in epithelial cells, miR-200c-3p did not target talin, a conformation activator of integrin, but, targeted E26-transformation-specific sequence 1 (ETS1), a transcriptional activator of α4 integrin, in T cells. Treatment of the miR-200c-3p-low-expressing TK-1 cells that possessed elevated α4 integrin with ETS1 small interfering RNA (siRNA) resulted in the reversion of the α4 integrin expression, supporting that ETS1 is a target of miR-200c-3p. A potential proinflammatory immune-modulator retinoic acid (RA) treatment of TK-1 cells elicited a significant reduction of miR-200c-3p and simultaneously a marked increase in ETS1 and α4 integrin expression. An anti-inflammatory cytokine TGF-β1 treatment elevated miR-200c-3p, thereby downregulating ETS1 and α4 integrin expression. These results suggest that miR-200c-3p is an important regulator of α4 integrin expression and functions and may be controlled by RA and TGF-β1 in an opposite way. Overexpression of miR-200c-3p could be a novel therapeutic option for treatment of gut inflammation through suppressing α4 integrin-mediated T cell migration.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer sub-type with limited treatment options and poor prognosis. Currently, standard treatments for TNBC include surgery, chemotherapy, and anti-PDL1 therapy. These therapies have limited efficacy in advanced stages. Myeloid-cell leukemia 1 (MCL1) is an anti-apoptotic BCL2 family protein. High expression of MCL1 contributes to chemotherapy resistance and is associated with a worse prognosis in TNBC. MCL1 inhibitors are in clinical trials for TNBC, but response rates to these inhibitors can vary and predictive markers are lacking. Currently, we identified a 4-member (AXL, ETS1, IL6, EFEMP1) gene signature (GS) that predicts MCL1 inhibitor sensitivity in TNBC cells. Factors encoded by these genes regulate signaling pathways to promote MCL1 inhibitor resistance. Small molecule inhibitors of the GS factors can overcome resistance and sensitize otherwise resistant TNBC cells to MCL1 inhibitor treatment. These findings offer insights into potential therapeutic strategies and tumor stratification for MCL1 inhibitor use in TNBC.

UNASSIGNED: This study aimed to investigate the mechanism of long noncoding ribonucleic acid (lncRNA) SNHG16 on kidney clear cell carcinoma (KIRC) cells by targeting miR-506-3p/ETS proto-oncogene 1, transcription factor (ETS1)/RAS/Extracellular regulated protein kinases (ERK) molecular axis, thus to provide reference for clinical diagnosis and treatment of KIRC in the future.
UNASSIGNED: Thirty-six patients with KIRC were enrolled in this study, and their carcinoma tissues and adjacent tissues were obtained for the detection of SNHG16/miR-506-3p/ETS1/RAS/ERK expression. Then, over-expressed SNHG16 plasmid and silenced plasmid were transfected into KIRC cells to observe the changes of their biological behavior.
UNASSIGNED: SNHG16 and ETS1 were highly expressed while miR-506- 3p was low expressed in KIRC tissues; the RAS/ERK signaling pathway was significantly activated in KIRC tissues (P < 0.05). After SNHG16 silence, KIRC cells showed decreased proliferation, invasion and migration capabilities and increased apoptosis rate; correspondingly, increase in SNHG16 expression achieved opposite results (P < 0.05). Finally, in the rescue experiment, the effects of elevated SNHG16 on KIRC cells were reversed by simultaneous increase in miR-506-3p, and the effects of miR-506-3p were reversed by ETS1. Activation of the RAS/ERK pathway had the same effect as increase in ETS1, which further worsened the malignancy of KIRC. After miR-506-3p increase and ETS1 silence, the RAS/ERK signaling pathway was inhibited (P < 0.05). At last, the rescue experiment (co-transfection) confirmed that the effect of SNHG16 on KIRC cells is achieved via the miR-506-3p/ETS1/RAS/ERK molecular axis.
UNASSIGNED: SNHG16 regulates the biological behavior of KIRC cells by targeting the miR-506-3p/ETS1/RAS/ERK molecular axis.