Skip to main content
Top
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Hepatocellular Carcinoma | Research

UTP11 promotes the growth of hepatocellular carcinoma by enhancing the mRNA stability of Oct4

Authors: Yan Chen, Xiaowei Zhang, Mingcheng Zhang, Wenting Fan, Yueyue Lin, Guodong Li

Published in: BMC Cancer | Issue 1/2024

Login to get access

Abstract

Background

Several publications suggest that UTP11 may be a promising gene engaged for involvement of hepatocellular carcinoma (HCC) pathology. However, there are extremely limited biological, mechanistic and clinical studies of UTP11 in HCC.

Methods

To anayze the UTP11 mRNA expression in HCC and normal clinical samples and further investigate the correlation between UTP11 expression and pathology and clinical prognosis via the Cancer Tissue Gene Atlas (TCGA) database. The protein levels of UTP11 were checked using the Human Protein Atlas (HPA) database. GO-KEGG enrichment was performed from Cancer Cell Line Encyclopedia (CCLE) database and TCGA dataset. The levels of UTP11 were tested with qRT-PCR and western blotting assays. Cell viability, immunofluorescence and flow cytometry assays and animal models were used to explore the potential involvement of UTP11 in regulating HCC growth in vitro and in vivo. The correlation of UTP11 and tumor stemness scores and stemness-associated proteins from TCGA database. The mRNA stability was treated with Actinomycin D, followed by testing the mRNA expression using qRT-PCR assay.

Results

UTP11 was highly expressed in HCC samples compared to normal tissues from TCGA database. Similarly, UTP11 protein expression levels were obviously elevated in HCC tissue samples from HPA database. Furthermore, UTP11 levels were correlated with poor prognosis in HCC patient samples in TCGA dataset. In addition, the UTP11 mRNA levels was notably enhanced in different HCC cell lines than in normal liver cells and knocking down UTP11 was obviously reduced the viability and cell death of HCC cells. UTP11 knockdown suppressed the tumor growth of HCC in vivo experiment and extended the mice survival time. GO-KEEG analysis from CCLE and TCGA database suggested that UTP11 might involve in RNA splicing and the stability of mRNA. Further, UTP11 was positively correlated with tumor stemness scores and stemness-associated proteins from TCGA database. Knockdown of UTP11 was reduced the expression of stem cell-related genes and regulated the mRNA stability of Oct4.

Conclusions

UTP11 is potentially a diagnostic molecule and a therapeutic candidate for treatment of HCC.
Appendix
Available only for authorised users
Literature
1.
go back to reference Craig AJ, Von Felden J, Garcia-Lezana T, Sarcognato S, Villanueva A. Tumour evolution in hepatocellular carcinoma. Nat Reviews Gastroenterol Hepatol. 2020;17(3):139–52.CrossRef Craig AJ, Von Felden J, Garcia-Lezana T, Sarcognato S, Villanueva A. Tumour evolution in hepatocellular carcinoma. Nat Reviews Gastroenterol Hepatol. 2020;17(3):139–52.CrossRef
3.
go back to reference Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6.PubMedCrossRef Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6.PubMedCrossRef
4.
go back to reference El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet. 2017;389(10088):2492–502.CrossRef El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet. 2017;389(10088):2492–502.CrossRef
5.
go back to reference Lopez de Andres J, Grinan-Lison C, Jimenez G, Marchal JA. Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment. J Hematol Oncol. 2020;13(1):136.PubMedPubMedCentralCrossRef Lopez de Andres J, Grinan-Lison C, Jimenez G, Marchal JA. Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment. J Hematol Oncol. 2020;13(1):136.PubMedPubMedCentralCrossRef
6.
go back to reference Lee TK, Guan XY, Ma S. Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol. 2022;19(1):26–44.PubMedCrossRef Lee TK, Guan XY, Ma S. Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol. 2022;19(1):26–44.PubMedCrossRef
7.
go back to reference Duan H, Liu Y, Gao Z, Huang W. Recent advances in drug delivery systems for targeting cancer stem cells. Acta Pharm Sin B. 2021;11(1):55–70.PubMedCrossRef Duan H, Liu Y, Gao Z, Huang W. Recent advances in drug delivery systems for targeting cancer stem cells. Acta Pharm Sin B. 2021;11(1):55–70.PubMedCrossRef
8.
go back to reference Liu YC, Yeh CT, Lin KH. Cancer Stem Cell functions in Hepatocellular Carcinoma and Comprehensive therapeutic strategies. Cells. 2020;9(6). Liu YC, Yeh CT, Lin KH. Cancer Stem Cell functions in Hepatocellular Carcinoma and Comprehensive therapeutic strategies. Cells. 2020;9(6).
9.
go back to reference Zhou JN, Zhang B, Wang HY, Wang DX, Zhang MM, Zhang M, et al. A functional screening identifies a new Organic selenium compound Targeting Cancer Stem cells: role of c-Myc transcription activity inhibition in Liver Cancer. Adv Sci (Weinh). 2022;9(22):e2201166.PubMedCrossRef Zhou JN, Zhang B, Wang HY, Wang DX, Zhang MM, Zhang M, et al. A functional screening identifies a new Organic selenium compound Targeting Cancer Stem cells: role of c-Myc transcription activity inhibition in Liver Cancer. Adv Sci (Weinh). 2022;9(22):e2201166.PubMedCrossRef
10.
go back to reference Heese K, Nakayama T, Hata R, Masumura M, Akatsu H, Li F, et al. Characterizing CGI-94 (comparative gene identification-94) which is down-regulated in the hippocampus of early stage Alzheimer’s disease brain. Eur J Neurosci. 2002;15(1):79–86.PubMedCrossRef Heese K, Nakayama T, Hata R, Masumura M, Akatsu H, Li F, et al. Characterizing CGI-94 (comparative gene identification-94) which is down-regulated in the hippocampus of early stage Alzheimer’s disease brain. Eur J Neurosci. 2002;15(1):79–86.PubMedCrossRef
11.
go back to reference Lai CH, Chou CY, Ch’ang LY, Liu CS, Lin W. Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res. 2000;10(5):703–13.PubMedPubMedCentralCrossRef Lai CH, Chou CY, Ch’ang LY, Liu CS, Lin W. Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res. 2000;10(5):703–13.PubMedPubMedCentralCrossRef
12.
go back to reference Barandun J, Hunziker M, Klinge S. Assembly and structure of the SSU processome-a nucleolar precursor of the small ribosomal subunit. Curr Opin Struct Biol. 2018;49:85–93.PubMedPubMedCentralCrossRef Barandun J, Hunziker M, Klinge S. Assembly and structure of the SSU processome-a nucleolar precursor of the small ribosomal subunit. Curr Opin Struct Biol. 2018;49:85–93.PubMedPubMedCentralCrossRef
13.
go back to reference Shi L, Shang X, Nie K, Lin Z, Zheng M, Wang M, et al. Identification of potential crucial genes associated with the pathogenesis and prognosis of liver hepatocellular carcinoma. J Clin Pathol. 2021;74(8):504–12.PubMedCrossRef Shi L, Shang X, Nie K, Lin Z, Zheng M, Wang M, et al. Identification of potential crucial genes associated with the pathogenesis and prognosis of liver hepatocellular carcinoma. J Clin Pathol. 2021;74(8):504–12.PubMedCrossRef
14.
go back to reference Zhang Y, Wang Y, Liu H, Li B. Six genes as potential diagnosis and prognosis biomarkers for hepatocellular carcinoma through data mining. J Cell Physiol. 2019;234(6):9787–92.PubMedCrossRef Zhang Y, Wang Y, Liu H, Li B. Six genes as potential diagnosis and prognosis biomarkers for hepatocellular carcinoma through data mining. J Cell Physiol. 2019;234(6):9787–92.PubMedCrossRef
15.
go back to reference Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BV, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8):649–58.PubMedPubMedCentralCrossRef Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BV, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8):649–58.PubMedPubMedCentralCrossRef
17.
go back to reference Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023;51(D1):D587–D92.PubMedCrossRef Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023;51(D1):D587–D92.PubMedCrossRef
19.
go back to reference Dib L, San-Jose LM, Ducrest A-L, Salamin N, Roulin A. Selection on the major color gene melanocortin-1-receptor shaped the evolution of the melanocortin system genes. Int J Mol Sci. 2017;18(12):2618.PubMedPubMedCentralCrossRef Dib L, San-Jose LM, Ducrest A-L, Salamin N, Roulin A. Selection on the major color gene melanocortin-1-receptor shaped the evolution of the melanocortin system genes. Int J Mol Sci. 2017;18(12):2618.PubMedPubMedCentralCrossRef
20.
go back to reference Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357(6352):eaan2507.PubMedCrossRef Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357(6352):eaan2507.PubMedCrossRef
21.
go back to reference Thul PJ, Åkesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al. A subcellular map of the human proteome. Science. 2017;356(6340):eaal3321.PubMedCrossRef Thul PJ, Åkesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al. A subcellular map of the human proteome. Science. 2017;356(6340):eaal3321.PubMedCrossRef
22.
go back to reference Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.PubMedCrossRef Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.PubMedCrossRef
23.
go back to reference Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603–7.PubMedPubMedCentralCrossRef Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603–7.PubMedPubMedCentralCrossRef
24.
go back to reference Fu J, Wang H. Precision diagnosis and treatment of liver cancer in China. Cancer Lett. 2018;412:283–8.PubMedCrossRef Fu J, Wang H. Precision diagnosis and treatment of liver cancer in China. Cancer Lett. 2018;412:283–8.PubMedCrossRef
25.
go back to reference Johnson P, Zhou Q, Dao DY, Lo YMD. Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2022;19(10):670–81.PubMedCrossRef Johnson P, Zhou Q, Dao DY, Lo YMD. Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2022;19(10):670–81.PubMedCrossRef
26.
go back to reference Sun D, Qin L, Xu Y, Liu JX, Tian LP, Qian HX. Influence of adriamycin on changes in nanog, Oct-4, Sox2, ARID1 and Wnt5b expression in liver cancer stem cells. World J Gastroenterol. 2014;20(22):6974–80.PubMedPubMedCentralCrossRef Sun D, Qin L, Xu Y, Liu JX, Tian LP, Qian HX. Influence of adriamycin on changes in nanog, Oct-4, Sox2, ARID1 and Wnt5b expression in liver cancer stem cells. World J Gastroenterol. 2014;20(22):6974–80.PubMedPubMedCentralCrossRef
27.
go back to reference Kuo KK, Lee KT, Chen KK, Yang YH, Lin YC, Tsai MH, et al. Positive Feedback Loop of OCT4 and c-JUN expedites Cancer Stemness in Liver Cancer. Stem Cells. 2016;34(11):2613–24.PubMedCrossRef Kuo KK, Lee KT, Chen KK, Yang YH, Lin YC, Tsai MH, et al. Positive Feedback Loop of OCT4 and c-JUN expedites Cancer Stemness in Liver Cancer. Stem Cells. 2016;34(11):2613–24.PubMedCrossRef
28.
go back to reference Zhang C, Huang S, Zhuang H, Ruan S, Zhou Z, Huang K, et al. YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. Oncogene. 2020;39(23):4507–18.PubMedCrossRef Zhang C, Huang S, Zhuang H, Ruan S, Zhou Z, Huang K, et al. YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. Oncogene. 2020;39(23):4507–18.PubMedCrossRef
30.
go back to reference Martin-Tumasz S, Richie AC, Clos LJ, Brow DA, Butcher SE. A novel occluded RNA recognition motif in Prp24 unwinds the U6 RNA internal stem loop. Nucleic Acids Res. 2011;39(17):7837–47.PubMedPubMedCentralCrossRef Martin-Tumasz S, Richie AC, Clos LJ, Brow DA, Butcher SE. A novel occluded RNA recognition motif in Prp24 unwinds the U6 RNA internal stem loop. Nucleic Acids Res. 2011;39(17):7837–47.PubMedPubMedCentralCrossRef
31.
32.
go back to reference El Fatimy R, Zhang Y, Deforzh E, Ramadas M, Saravanan H, Wei Z, et al. A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing. Mol Cancer. 2022;21(1):17.PubMedPubMedCentralCrossRef El Fatimy R, Zhang Y, Deforzh E, Ramadas M, Saravanan H, Wei Z, et al. A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing. Mol Cancer. 2022;21(1):17.PubMedPubMedCentralCrossRef
33.
go back to reference Galej WP, Toor N, Newman AJ, Nagai K. Molecular mechanism and evolution of nuclear pre-mRNA and group II intron splicing: insights from cryo-electron microscopy structures. Chem Rev. 2018;118(8):4156–76.PubMedCrossRef Galej WP, Toor N, Newman AJ, Nagai K. Molecular mechanism and evolution of nuclear pre-mRNA and group II intron splicing: insights from cryo-electron microscopy structures. Chem Rev. 2018;118(8):4156–76.PubMedCrossRef
34.
go back to reference Townsend C, Leelaram MN, Agafonov DE, Dybkov O, Will CL, Bertram K, et al. Mechanism of protein-guided folding of the active site U2/U6 RNA during spliceosome activation. Science. 2020;370(6523):eabc3753.PubMedCrossRef Townsend C, Leelaram MN, Agafonov DE, Dybkov O, Will CL, Bertram K, et al. Mechanism of protein-guided folding of the active site U2/U6 RNA during spliceosome activation. Science. 2020;370(6523):eabc3753.PubMedCrossRef
35.
go back to reference Teplova M, Patel DJ. Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1. Nat Struct Mol Biol. 2008;15(12):1343–51.PubMedPubMedCentralCrossRef Teplova M, Patel DJ. Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1. Nat Struct Mol Biol. 2008;15(12):1343–51.PubMedPubMedCentralCrossRef
36.
go back to reference Cazalla D, Newton K, Cáceres JF. A novel SR-related protein is required for the second step of Pre-mRNA splicing. Mol Cell Biol. 2005;25(8):2969–80.PubMedPubMedCentralCrossRef Cazalla D, Newton K, Cáceres JF. A novel SR-related protein is required for the second step of Pre-mRNA splicing. Mol Cell Biol. 2005;25(8):2969–80.PubMedPubMedCentralCrossRef
37.
go back to reference Najafi M, Farhood B, Mortezaee K. Cancer stem cells (CSCs) in cancer progression and therapy. J Cell Physiol. 2019;234(6):8381–95.PubMedCrossRef Najafi M, Farhood B, Mortezaee K. Cancer stem cells (CSCs) in cancer progression and therapy. J Cell Physiol. 2019;234(6):8381–95.PubMedCrossRef
38.
go back to reference Barzegar Behrooz A, Syahir A, Ahmad S. CD133: beyond a cancer stem cell biomarker. J Drug Target. 2019;27(3):257–69.PubMedCrossRef Barzegar Behrooz A, Syahir A, Ahmad S. CD133: beyond a cancer stem cell biomarker. J Drug Target. 2019;27(3):257–69.PubMedCrossRef
39.
go back to reference Park DJ, Sung PS, Kim JH, Lee GW, Jang JW, Jung ES et al. EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1. J Immunother Cancer. 2020;8(1). Park DJ, Sung PS, Kim JH, Lee GW, Jang JW, Jung ES et al. EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1. J Immunother Cancer. 2020;8(1).
40.
go back to reference Liu B, Fang X, Kwong DL, Zhang Y, Verhoeft K, Gong L, et al. Targeting TROY-mediated P85a/AKT/TBX3 signaling attenuates tumor stemness and elevates treatment response in hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41(1):182.PubMedPubMedCentralCrossRef Liu B, Fang X, Kwong DL, Zhang Y, Verhoeft K, Gong L, et al. Targeting TROY-mediated P85a/AKT/TBX3 signaling attenuates tumor stemness and elevates treatment response in hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41(1):182.PubMedPubMedCentralCrossRef
42.
go back to reference Dai X, Guo Y, Hu Y, Bao X, Zhu X, Fu Q, et al. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics. 2021;11(7):3489–501.PubMedPubMedCentralCrossRef Dai X, Guo Y, Hu Y, Bao X, Zhu X, Fu Q, et al. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics. 2021;11(7):3489–501.PubMedPubMedCentralCrossRef
44.
go back to reference Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2. 0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48(W1):W509–W14.PubMedPubMedCentralCrossRef Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2. 0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48(W1):W509–W14.PubMedPubMedCentralCrossRef
Metadata
Title
UTP11 promotes the growth of hepatocellular carcinoma by enhancing the mRNA stability of Oct4
Authors
Yan Chen
Xiaowei Zhang
Mingcheng Zhang
Wenting Fan
Yueyue Lin
Guodong Li
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11794-2

Other articles of this Issue 1/2024

BMC Cancer 1/2024 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine