C/EBPα-p30 protein induces expression of the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia

Accumulating evidences indicate that different long non-coding RNAs (lncRNAs) might play a relevant role in tumorigenesis, with their expression and function already associated to cancer development and progression. CCAAT/enhancer-binding protein-α (CEBPA) is a critical regulator of myeloid differentiation whose inactivation contributes to the development of acute myeloid leukemia (AML). Mutations in C/EBPα occur in around 10% of AML cases, leading to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30). In this study, we identified the oncogenic urothelial carcinoma associated 1 (UCA1) lncRNA as a novel target of the C/EBPα-p30. We show that wild-type C/EBPα and C/EBPα-p30 isoform can bind the UCA1 promoter but have opposite effects on UCA1 expression. While wild-type C/EBPα represses, C/EBPα-p30 can induce UCA1 transcription. Notably, we also show that UCA1 expression increases in cytogenetically normal AML cases carrying biallelic CEBPA mutations. Furthermore, we demonstrate that UCA1 sustains proliferation of AML cells by repressing the expression of the cell cycle regulator p27kip1. Thus, we identified, for the first time, an oncogenic lncRNA functioning in concert with the dominant negative isoform of C/EBPα in AML

Overexpression of lncRNA UCA1 promotes osteosarcoma progression and correlates with poor prognosis

AbstractLong non-coding RNAs (lncRNAs) have been proved to play important roles in the tumorigenesis and development of several human malignancies. Our study aims to investigate the expression and function of lncRNA-UCA1 in osteosarcoma. lncRNA-UCA1 expression was detected in osteosarcoma tissues and cell lines by using qRT-PCR. Association between lncRNA-UCA1 levels and clinicopathological factors and patient's prognosis was analyzed. The roles of lncRNA-UCA1 in regulating osteosarcoma cell proliferation, apoptosis, migration, and invasion were evaluated in vitro. We found that lncRNA-UCA1 expression was upregulated in osteosarcoma tissues and cell lines. High lncRNA-UCA1 expression was significantly correlated with large tumor size, high tumor grade, positive distant metastasis, and advanced clinical stage. Multivariate regression analysis identified lncRNA-UCA1 overexpression as an independent unfavorable prognostic factor. lncRNA-UCA1 knockdown inhibited osteosarcoma cell proliferation, promoted cell apoptosis, and suppressed cell invasion and migration, whereas lncRNA-UCA1 overexpression showed opposite effects. These findings suggested that lncRNA-UCA1 may contribute to osteosarcoma initiation and progression, and would be not only a novel prognostic marker but also a potential therapeutic target for this disease

LncRNAs: the bridge linking RNA and colorectal cancer.

Long noncoding RNAs (lncRNAs) are transcribed by genomic regions (exceeding 200 nucleotides in length) that do not encode proteins. While the exquisite regulation of lncRNA transcription can provide signals of malignant transformation, lncRNAs control pleiotropic cancer phenotypes through interactions with other cellular molecules including DNA, protein, and RNA. Recent studies have demonstrated that dysregulation of lncRNAs is influential in proliferation, angiogenesis, metastasis, invasion, apoptosis, stemness, and genome instability in colorectal cancer (CRC), with consequent clinical implications. In this review, we explicate the roles of different lncRNAs in CRC, and the potential implications for their clinical application

Super-Enhancer-Associated LncRNA UCA1 Interacts Directly with AMOT to Activate YAP Target Genes in Epithelial Ovarian Cancer

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of tumorigenesis, and yet their mechanistic roles remain challenging to characterize. Here, we integrate functional proteomics with lncRNA-interactome profiling to characterize Urothelial Cancer Associated 1 (UCA1), a candidate driver of ovarian cancer development. Reverse phase protein array (RPPA) analysis indicates that UCA1 activates transcription coactivator YAP and its target genes. In vivo RNA antisense purification (iRAP) of UCA1 interacting proteins identified angiomotin (AMOT), a known YAP regulator, as a direct binding partner. Loss-of-function experiments show that AMOT mediates YAP activation by UCA1, as UCA1 enhances the AMOT-YAP interaction to promote YAP dephosphorylation and nuclear translocation. Together, we characterize UCA1 as a lncRNA regulator of Hippo-YAP signaling and highlight the UCA1-AMOT-YAP signaling axis in ovarian cancer development

Long non-coding RNAs in cutaneous melanoma : clinical perspectives

Metastatic melanoma of the skin has a high mortality despite the recent introduction of targeted therapy and immunotherapy. Long non-coding RNAs (lncRNAs) are defined as transcripts of more than 200 nucleotides in length that lack protein-coding potential. There is growing evidence that lncRNAs play an important role in gene regulation, including oncogenesis. We present 13 lncRNA genes involved in the pathogenesis of cutaneous melanoma through a variety of pathways and molecular interactions. Some of these lncRNAs are possible biomarkers or therapeutic targets for malignant melanoma

LncRNA Impact on Regorafenib Resistance in Colorectal Cancer

Cancer metastasis is one of the deadliest aspects of the disease, with about 90% of all cancer-related deaths due to its development at different sites within the body. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States, with 40-50% of all patients developing metastasis at some point during their fight with the disease. With the approval of Regorafenib for treating metastatic colorectal cancer, steps have been taken to combat metastasis in colorectal cancer. A vital aspect of the development of metastasis is the development of resistance to first-line chemotherapy. Regorafenib is an oral small-molecule multiple kinase inhibitor. It is indicated worldwide for patients with metastatic colorectal cancer (mCRC), Regorafenib has already begun to show resistance in CRC. Understanding the mechanisms behind Regorafenib resistance in CRC is vital. Studies have demonstrated the expression of Long-non-coding RNA (LncRNA) to be linked to cancer metastasis and drug resistance. LncRNA UCA1 has been shown in other cancers to lead to resistance to different drugs like cisplatin, gemcitabine, 5-FU, tamoxifen, imatinib, and EGFR-TKIs. In our lab, we have found the LncRNA UCA1 to be overexpressed in CRC patient tissues, with increasing expression across stages I-III, compared to normal tissue. High UCA1 expression has decreased survival among colorectal cancer patients, per the TCGA patient cohort analysis. Furthermore, we found that high UCA1 expression in colorectal cancer cell lines leads to high IC50 values for Regorafenib. Lentiviral transduce stable overexpression (SW480), and knockdown (SW620) cell lines were developed and are being used for UCA1-regorafenib drug resistance mechanistic studies. Increased expression of UCA1 led to increased expression of crucial drug resistance genes (MDR1, ABCB1, and FOXM1) and increased IC50 compared to the control vector. A 3D spheroid model was utilized to assay regorafenib sensitivity to the UCA1 overexpressed cell lines. High UCA1 expression leads to the formation of a higher number of 3D spheroid bodies and size when compared to vector. We treated the spheroid with IC50 concentration, and data will be presented. We also plan to study the lncRNA UCA1 associated Regorafenib resistance in the SW620 knockdown cell lines. In future, we will also analyze the signaling pathways modulated by UCA1 in CRC cell lines, which may be involved in enhancing the regorafenib resistance. This supports the notion that UCA1 is critical in enhancing the resistance to regorafenib in CRC by activating drug resistance pathways. For the first time, this study demonstrates that UCA1 provides drug resistance to regorafenib in CRC, facilitating the progression of CRC metastasis

The Challenges and Opportunities of lncRNAs in Ovarian Cancer Research and Clinical Use

[Abstract] Ovarian cancer is one of the most lethal gynecological malignancies worldwide because it tends to be detected late, when the disease has already spread, and prognosis is poor. In this review we aim to highlight the importance of long non-coding RNAs (lncRNAs) in diagnosis, prognosis and treatment choice, to make progress towards increasingly personalized medicine in this malignancy. We review the effects of lncRNAs associated with ovarian cancer in the context of cancer hallmarks. We also discuss the molecular mechanisms by which lncRNAs become involved in cellular physiology; the onset, development and progression of ovarian cancer; and lncRNAs’ regulatory mechanisms at the transcriptional, post-transcriptional and post-translational stages of gene expression. Finally, we compile a series of online resources useful for the study of lncRNAs, especially in the context of ovarian cancer. Future work required in the field is also discussed along with some concluding remarks.This work was funded by Plan Estatal I + D + I by the Instituto de Salud Carlos III (ISCIII, Spain) under grant agreement AES number PI18/01714, cofounded by Fondo Europeo de Desarrollo Regional-FEDER (The European Regional Development Fund-ERDF) “A way of Making Europe,” and by Xunta de Galicia (Consolidación Grupos Referencia Competitiva contract number ED431C 2016-012). M.S.M. was funded by a predoctoral fellowship from FPU-2018 (Spain)Xunta de Galicia; ED431C 2016-01

Aspects of Glucose Metabolism in Anoikis-induced Colorectal Cells

Colorectal cancer (CRC) is the second most lethal cancer, and its survival rate drops from 90% to 14% when the condition is contained within the colon vs. when found at distant sites within the body. This is concerning because the disease will develop metastasis in 40-50% of patients. Metastasis is a multistep process in which cancer cells gain anoikis resistance to survive after detaching from primary locations and traveling through the circulatory and lymphatic systems to distant target organs. Thus, understanding the molecular drivers involved in glucose metabolism and its role in the anoikis process could be vital for improving the survival of CRC patients. Long non-coding RNA (lncRNA) is a class of RNA that does not directly code for protein but can hold many different roles in the cell. The lncRNA urothelial carcinoma-associated 1 (UCA1) aberrant expression has been identified in CRC and is associated with a poor prognosis. However, its function in glucose metabolism processes is not yet well defined. Our preliminary results in the anchorage-independent growth (anoikis) model demonstrate increased expression of lncRNA UCA1 and glucose uptake. Not only did the overexpression of lncRNA UCA1 lead to higher glucose consumption, but it also had an increased survival of anchorage-independent cells, which could indicate a potential mechanistic role of UCA1 in the modulation of glucose metabolism. Therefore, in this study, we propose elucidating the role(s) of UCA1 and its association with glucose metabolism during anoikis resistance. We hypothesize that the overexpression of lncRNA UCA1 enhances CRC metastasis by changing the glucose metabolism and, therefore, its anoikis resistance-associated pathways. We will utilize isogenic CRC cell lines SW480 (oncogenic) and SW620 (metastatic) to understand the mechanistic regulation of anoikis resistance. Stable overexpression (SW480+UCA1//GFP) and knockdown (SW620+ShUCA1) cell lines have been utilized for this study; both puromycin were selected and sorted. After subjecting these cell lines (along with the respective control) to anchorage-independent growth conditions, glucose pathway markers, pro-survival, anti-apoptotic, and stemness factors will be analyzed through RT-PCR, western blot, and Seahorse analyses. Utilizing the same model, we will examine lncRNA UCA1 linked anoikis resistance specific phosphorylation profiles of kinases and their protein substrates using the Proteome Profiler Phospho-Human Phospho-Kinase Array

The altered expression of long non-coding RNAs: GHET1, BACE1-AS, PANDA, UCA1 associated with non-small cell lung cancer

Objective: Long non-coding RNAs (lncRNAs) are characterized as non-coding transcripts greater than 200 nucleotides. lncRNAs have extensive molecular connections with proteins and microRNAs, which are important in the regulation of gene expression in physiologic and pathologic states including cancer. About 18% of human LncRNAs were recently found to be associated with tumours. Many studies indicated that aberrant expression of LncRNAs play key roles in the progression and metastasis of NSCLC. In this study we evaluated the expression of long non-coding RNAs: GHET1, BACE1-AS, PANDA, UCA1 in non-small cell lung cancer. Material & Methods: In this study, RNA was extracted from tumor tissues of NSCLC and paired adjacent normal lung tissues. After cDNA synthesis, the relative expression level of lncRNA GHET1, BACE1-AS, PANDA, and UCA1 genes was studied by TaqMan Real-Time PCR, and the data were analyzed by 2-∆∆CT. The t-test was used to compare the values and P-value < 0.05 was considered statistically significant. Results: The data of qRT-PCR analysis revealed that the expression level of GHET1 gene in patients with NSCLC is increased (P= 0.0032) and BACE1-AS showed down-regulation (P= 0.0093). There was no significant change in the expression of PANDA and UCA1 genes. Conclusion: Our study sheds lights on the expression signature of several crucial lncRNAs in human lung cancer. This data not only could be further be utilized for different therapeutic approaches but also reveal the changes in biological processes of human lung tumors. &nbsp