Dataset Information

H19: An Oncogenic Long Non-coding RNA in Colorectal Cancer.

ABSTRACT: Colorectal cancer (CRC) has been recorded amongst the most common cancers in the world, with high morbidity and mortality rates, and relatively low survival rates. With risk factors such as chronic illness, age, and lifestyle associated with the development of CRC, the incidence of CRC is increasing each year. Thus, the discovery of novel biomarkers to improve the diagnosis and prognosis of CRC has become beneficial. Long non-coding RNAs (lncRNAs) have been emerging as potential players in several tumor types, one among them is the lncRNA H19. The paternally imprinted oncofetal gene is expressed in the embryo, downregulated at birth, and reappears in tumors. H19 aids in CRC cell growth, proliferation, invasion, and metastasis via various mechanisms of action, significantly through the lncRNA-microRNA (miRNA)-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network, where H19 behaves as a miRNA sponge. The RNA transcript of H19 obtained from the first exon of the H19 gene, miRNA-675 also promotes CRC carcinogenesis. Overexpression of H19 in malignant tissues compared to adjacent non-malignant tissues marks H19 as an independent prognostic marker in CRC. Besides its prognostic value, H19 serves as a promising target for therapy in CRC treatment.

SUBMITTER: Chowdhury PR

PROVIDER: S-EPMC10751868 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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H19: An Oncogenic Long Non-coding RNA in Colorectal Cancer.

Chowdhury Prerana R PR Salvamani Shamala S Gunasekaran Baskaran B Peng Hoh B HB Ulaganathan Vaidehi V

The Yale journal of biology and medicine 20231229 4

Colorectal cancer (CRC) has been recorded amongst the most common cancers in the world, with high morbidity and mortality rates, and relatively low survival rates. With risk factors such as chronic illness, age, and lifestyle associated with the development of CRC, the incidence of CRC is increasing each year. Thus, the discovery of novel biomarkers to improve the diagnosis and prognosis of CRC has become beneficial. Long non-coding RNAs (lncRNAs) have been emerging as potential players in sever ...[more]

PMID: 38161577

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Project description:Introduction: Long non-coding RNA H19 (lncH19) is highly expressed in colorectal cancer (CRC) and plays critical roles in tumor development, proliferation, metastasis, and drug resistance. Indeed, the expression of lncH19 usually affects the outcomes of chemo-, endocrine, and targeted therapies. ITF2357 (givinostat) is a histone deacetylase inhibitor (HDACi) that revealed a significant anti-tumor action by inducing apoptosis in different tumor models, including leukemia, melanoma, and glioblastoma. However, no data are present in the literature regarding the use of this compound for CRC treatment. Here, we investigate the role of lncH19 in ITF2357-induced apoptosis in CRC cells. Methods: The HCT-116 CRC cell line was stably silenced for H19 to investigate the role of this lncRNA in ITF2357-induced cell death. Cell viability assays and flow cytometric analyses were performed to assess the anti-proliferative and pro-apoptotic effects of ITF2357 in CRC cell lines that are silenced or not for lncH19. RT-PCR and Western blot were used to study the effects of ITF2357 on autophagy and apoptosis markers. Finally, bioinformatics analyses were used to identify miRNAs targeting pro-apoptotic factors that can be sponged by lncH19. Results: ITF2357 increased the expression levels of H19 and reduced HCT-116 cell viability, inducing apoptosis, as demonstrated by the increase in annexin-V positivity, caspase 3 cleavage, and poly (ADP-ribose) polymerase (PARP-1) degradation. Interestingly, the apoptotic effect of ITF2357 was much less evident in lncH19-silenced cells. We showed that lncH19 plays a functional role in the pro-apoptotic activity of the drug by stabilizing TP53 and its transcriptional targets, NOXA and PUMA. ITF2357 also induced autophagy in CRC cells, which was interpreted as a pro-survival response not correlated with lncH19 expression. Furthermore, ITF2357 induced apoptosis in 5-fluorouracil-resistant HCT-116 cells that express high levels of lncH19. Conclusion: This study shows that lncH19 expression contributes to ITF2357-induced apoptosis by stabilizing TP53. Overall, we suggest that lncH19 expression may be exploited to favor HDACi-induced cell death and overcome 5-fluorouracil chemoresistance.

Project description:Advanced gallbladder cancer (GBC) is one of the most malignant of all types of biliary tract cancers that is associated with poor prognosis and high mortality. Accumulating evidence suggest that the B7 family of proteins serve an essential role in various types of cancers, including GBC. However, the potential function and regulatory mechanism of human endogenous retrovirus‑H long terminal repeat‑associating protein 2 (HHLA2; also known as B7‑H7 or B7H5) in GBC remain poorly understood. In the present study, immunohistochemistry was used to examine the expression pattern of HHLA2 in samples from 89 patients with GBC. The possible association between HHLA2 expression and the clinicopathological parameters, including prognosis, were then assessed. Using lentiviruses, overexpression of HHLA2 plasmid or short‑hairpin RNA (shRNA) of HHLA2 were transfected into GBC‑SD cells to overexpress or knock down HHLA2 expression, respectively. The effects of HHLA2 overexpression and knockdown on the epithelial‑mesenchymal transition (EMT) process on GBC‑SD cells were measured by the western blotting and immunofluorescence staining of collagen I, N‑cadherin, E‑cadherin, vimentin and α‑SMA. By contrast, changes in cell proliferation were measured using EdU assay. Cell invasion and migration were assessed using Transwell and wound‑healing assays, respectively. In addition, a xenograft mouse model was established to evaluate the tumorigenic ability of the GBC cell line in vivo after stable transfection with lentivirus for HHLA2 overexpression or shRNA for HHLA2 knockdown. The regulatory relationships among TGF‑β1, long non‑coding RNA (lncRNA) H19 (H19) and HHLA2 were then investigated. The mRNA expression of lncRNA H19 were assessed using reverse transcription‑quantitative PCR, whereas the expression levels of HHLA2 were detected by western blotting and immunofluorescence staining. HHLA2 expression was found to gradually increase as the stages of the GBC samples become more advanced. In addition, the expression level of HHLA2 was calculated to be positively associated with the Nevin stage, American Joint Committee on Cancer stage, tumor invasion and regional lymph node metastasis but was negatively associated with the overall patient survival (OS). In vitro experiments demonstrated that overexpression of HHLA2 promoted GBC migration, invasion, proliferation and EMT, whereas in vivo experiments found a promoting role of HHLA2 overexpression on GBC tumor growth. After transfection with lentiviruses encoding the overexpression plasmid of lncRNA H19, GBC migration, invasion, proliferation and EMT were increased. By contrast, knocking down HHLA2 expression suppressed TGF‑β1‑ or lncRNA H19 overexpression‑induced GBC migration, invasion, proliferation and EMT. In addition, HHLA2 knockdown significantly reduced the sizes of the GBC tumors in vivo. These results suggest that HHLA2 overexpression can promote GBC progression. Conversely, ablation of HHLA2 expression inhibited both TGF‑β1‑ and lncRNA H19‑induced GBC progression, suggesting that HHLA2 is a potential therapeutic target for this disease.

Dataset Information

H19: An Oncogenic Long Non-coding RNA in Colorectal Cancer.

Publications

H19: An Oncogenic Long Non-coding RNA in Colorectal Cancer.

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