Role Of UCA1 Research Articles

TGF-β1/Smad3 upregulates UCA1 to promote liver fibrosis through DKK1 and miR18a.

TGF-β1 is the strongest cytokine known to promote liver fibrosis. It has been previously demonstrated that the activation of TGF-β1 initiates a temporary collagen accumulation program, which is important for wound repair in several organs. Furthermore, temporary extracellular matrix enhancement often leads to progressive fibrosis, which is accountable for cases of severe morbidity and mortality worldwide. However, its action mechanism has not been fully explored. It was previously reported that UCA1 could promote its occurrence and development in various tumors. Importantly, it was reported that TGF-β1 could activate the expression of UCA1 in liver cancer, gastric cancer, and breast cancer. However, the role of UCA1 in organ fibrosis, including liver fibrosis, remains unreported. The present study reported for the first time that TGF-β1/Smad3 could promote liver fibrosis by upregulating UCA1, which further affected DKK1 and collagen, such as COL1A1, COL1A2, and COL3A1. Meanwhile, UCA1 could competitively bind with miR18a to stabilize Smad3 to constitute a positive feedback pathway, which played a significant role in the promotion of liver fibrosis. Altogether, the present study provides a theoretical basis for devising promising treatment strategies for liver fibrosis. KEY MESSAGES : UCA1 was found to promote the progression of liver fibrosis in vitro. UCA1 is regulated by TGF-β1 and promotes liver fibrosis through the canonical Smad pathway. UCA1 can competitively bind with miR18a, promote liver fibrosis by stabilizing Smad3, and form a UCA1-miR18a/Smad3 positive feedback. UCA1 binds EZH2 to inhibit the DKK1 expression and promote liver fibrosis.

Genetic variations in UCA1, a lncRNA functioning as a miRNA sponge, determine endometriosis development and the potential associated infertility via regulating lipogenesis.

Endometriosis is a hormone-associated disease which has been considered as the precursor for certain types of ovarian cancer. In recent years, emerging evidence demonstrated potent roles of lncRNA in regulating cancer development. Since endometriosis shares several features with cancer, we investigated the possible involvement of cancer-related lncRNAs in endometriosis, including UCA1, GAS5 and PTENP1. By using massARRAY system, we investigated certain genetic variations in cancer-related lncRNAs that can change the thermo-stability, leading to up-regulation or down-regulation of those lncRNAs. Our data indicated three risk genetic haplotypes in UCA1 which can stabilize the RNA structure and increase the susceptibility of endometriosis. Of note, such alterations were found to be associated with long-term pain and infertility in patients. It has been known that UCA1 can function as a ceRNA to sponge and inhibit miRNAs, resulting in loss-of-control on downstream target genes. Gene network analyses revealed fatty acid metabolism and mitochondria beta-oxidation as the major pathways associated with altered UCA1 expression in endometriosis patients. Our study thus provides evidence to highlight functional/epigenetic roles of UCA1 in endometriosis development via regulating fatty acid metabolism in women.

Abstract 1547: LncRNA UCA1 modulates glucose metabolism proteins in colorectal cancer

Abstract Colorectal cancer (CRC) is the primary cause of cancer-related deaths worldwide. According to the American Cancer Society, it is the third most common cancer diagnosed in adults in the United States. It will have an estimated 149,500 new cases of colon cancer in 2021. In addition, studies show CRC has increased morbidity with obesity and obesity-related diseases such as diabetes. In a geographical area of The Rio Grande Valley which has a high incidence of diabetes, understanding the connection between CRC and diabetes is essential. Our lab identified LncRNA UCA1, a poor prognosis marker in CRC, responsible for increased proliferation and upregulating glucose metabolic pathway. First, we investigated the possible role of UCA1 in glucose metabolism, finding that UCA1 overexpressing cells (SW480+UCA1) showed a higher glucose consumption than their vector. The inverse of this trend was established when we knockdown UCA1 (SW620+shUCA1). Further, we found that overexpressing UCA1 increases the migration, invasion, and proliferation of SW480 cells. A vital aspect of the metastatic progression is when the cell survives detachment from the extracellular matrix. A route in which they overcome apoptosis is through modulation of the metabolic pathways, upregulating such markers as GLUT1, FDFT1, SGK1, and HIF1α. At 36hrs of anchorage-independent stimulation, we found an uptick in glucose consumption and lactate production and an increase in the expression of GLUT1, FDFT1, SGK1, and HIF1α compared to 0hrs. The Warburg effect is when glycolysis is no longer connected to the tricarboxylic acid cycle or oxidative phosphorylation. The increase in expression of the markers GLUT1, FDFT1, SGK1, and HIF1α indicates aerobic metabolic activity during anchorage-independent growth with UCA1 expression. This relationship needs to be further examined and could lead to understanding the increased morbidity associated with diabetes and CRC. Citation Format: Sophia Leslie, Kyle Doxtater, Samantha Lopez, Adithya Anilkumar, Meena Jaggi, Subhash Chauhan, Manish Tripathi. LncRNA UCA1 modulates glucose metabolism proteins in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1547.

Circulating lncRNA UCA1 Promotes Malignancy of Colorectal Cancer via the miR-143/MYO6 Axis

Exosomes mediate cell-cell crosstalk in cancer progression by transferring a variety of biomolecules, including long noncoding RNAs (lncRNAs). Long non-coding RNA urothelial carcinoma-associated (UCA1) is a well-known lncRNA associated with the development and progression of various cancers, including colorectal cancer (CRC). However, the presence of UCA1 in exosomes and the roles and clinical values of exosomal UCA1 in CRC remain unknown. In this study, we systematically analyzed the expression profiles of exosomal lncRNAs in CRC patients using a high-throughput microarray assay. Then, we evaluated the UCA1 expression levels in a series of CRC tissues and the serum exosomes of CRC patients using quantitative real-time PCR. The roles of UCA1 on CRC in vitro and in vivo were investigated by MTT, colony formation, Transwell, quantitative real-time PCR, flow cytometry, and western blotting. The miRNA binding sites of UCA1 were predicted using the miRcode online database, and miR-143 was validated to target UCA1 by dual-luciferase activity assay and AGO2 RNA immunoprecipitation. Finally, the role of exosome-mediated UCA1 was further investigated by co-culturing with CRC cells. This study showed that UCA1 was upregulated in CRC tissues and functioned as an oncogene in CRC. Loss-of-function investigations showed that inhibition of UCA1 suppressed CRC cell proliferation and metastasis in vivo and in vitro. Mechanistically, UCA1 was identified as a miR-143 sponge. We also found that MYO6 was a direct target of miR-1205, which functioned as an oncogene in CRC. Moreover, UCA was also upregulated in the serum exosomes of CRC patients and could transfer UCA1 to CRC cells to increase their abilities of cell proliferation and migration. In conclusion, these data suggest that UCA1 could be an oncogene for CRC and may serve as a candidate target for new therapies in human CRC.

LncRNA-UCA1 enhances MMP-13 expression by inhibiting miR-204-5p in human chondrocytes.

Osteoarthritis (OA) is a common degenerative disease characterized by degeneration of articular cartilage. Increasing studies showed that long noncoding RNAs (lncRNAs) play important roles in the cartilage damage. However, little is known about the role of UCA1 in the osteoarthritis. The expression level of UCA1 was upregulated in the OA cartilage. Overexpression of UCA1 suppressed the miR-204-5p expression in the chondrocytes. The expression of miR-204-5p was downregulated in the OA cartilage. Moreover, the expression of miR-204-5p was negatively correlated with the UCA1 expression in the OA cartilage. Elevated expression of UCA1 promoted the chondrocytes cell proliferation and overexpression of miR-204-5p suppressed chondrocytes cell proliferation. In addition, overexpression of UCA1 decreased the expression of the type II collagen and type IV collagen expression in the chondrocytes. Elevated expression of miR-204-5p promoted the type II collagen and type IV collagen expression in the chondrocytes. We idetified MMP-13 was a direct target gene of miR-204-5p in the chondrocytes. Overexpression of UCA1 enhanced the MMP-13 expression in the chondrocytes. Elevated expression of UCA1 regulated the chondrocytes cell proliferation and collagen expression through inhibiting the miR-204-5p expression.These results suggested that UCA1 played as an important regulator of survival and matrix synthesis of chondrocytes partly through suppressing the miR-204-5p expression.