Generic placeholder image

Current Cancer Drug Targets

Author(s): Zhelong Jiang, Zhihong Wei, Jianwei Chen, Fang Yang, Yi Jiang and Lizhi Lv*

DOI: 10.2174/1568009622666220901121641

DownloadDownload PDF Flyer Cite As
BZW2, CDT1 and IVD Act As Biomarkers for Predicting Hepatocellular Carcinoma

Page: [211 - 221] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths globally. This study aimed to provide a comprehensive investigation to screen and identify biomarkers for predicting HCC.

Methods: Firstly, the bioinformatics technique was applied to screen potential HCC-related genes, and the relationships between BZW2, CDT1, IVD expression and survival rate and clinicopathological factors were assessed. Afterward, qRT-PCR, western blot and immunohistochemistry were employed to validate the expression of BZW2, CDT1, and IVD in clinical resected cancer specimens. Furthermore, in vitro assays, cell cycle, apoptosis, colony formation and scratch experiments were performed to detect the effects of si-BZW2, si-CDT1 and oe-IVD in HCC cells. In vivo experiments, tumor volume and weight were measured to assess the anti-tumor effect of si-BZW2, si-CDT1 and oe-IVD in HCCtumor- bearing mice.

Results: Bioinformatics analysis indicated that HCC patients with high expression of BZW2, CDT1 and low expression of IVD have a poor prognosis and unfavorable clinicopathological factors. Similarly, clinical sample analysis revealed that BZW2 and CDT1 expression were increased while IVD expression was decreased in HCC tissues. Meanwhile, in vitro experiments found that si-BZW2, si- CDT1 and oe-IVD promoted apoptosis and inhibited the colony formation and migration of HCC cells. As expected, in vivo experiments demonstrated that si-BZW2, si-CDT1 and oe-IVD could inhibit tumor growth.

Conclusion: Increased BZW2, CDT1 levels, and decreased IVD levels could act as biomarkers for predicting HCC. Furthermore, targeting BZW2, CDT1, and IVD may offer a new approach to treat HCC.

Keywords: biomarkers, Hepatocellular carcinoma, BZW2, CDT1, IVD

Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Gnoni, A.; Santini, D.; Scartozzi, M.; Russo, A.; Licchetta, A.; Palmieri, V.; Lupo, L.; Faloppi, L.; Palasciano, G.; Memeo, V.; Angarano, G.; Brunetti, O.; Guarini, A.; Pisconti, S.; Lorusso, V.; Silvestris, N. Hepatocellular carcinoma treatment over sorafenib: Epigenetics, microRNAs and microenvironment. Is there a light at the end of the tunnel? Expert Opin. Ther. Targets, 2015, 19(12), 1623-1635.
[http://dx.doi.org/10.1517/14728222.2015.1071354] [PMID: 26212068]
[3]
Zhao, Z.; Xiong, S.; Wang, R.; Li, Y.; Wang, X.; Wang, Y.; Bai, S.; Chen, W.; Zhao, Y.; Cheng, B. Peri-tumor fibroblasts promote tumorigenesis and metastasis of hepatocellular carcinoma via Interleukin6/STAT3 signaling pathway. Cancer Manag. Res., 2019, 11, 2889-2901.
[http://dx.doi.org/10.2147/CMAR.S192263] [PMID: 31118769]
[4]
Lleo, A.; Aglitti, A.; Aghemo, A.; Maisonneuve, P.; Bruno, S.; Persico, M.; Rendina, M.; Ciancio, A.; Lampertico, P.; Brunetto, M.R.; Di Marco, V.; Zuin, M.; Andreone, P.; Villa, E.; Troshina, G.; Degasperi, E.; Coco, B.; Calvaruso, V.; Giorgini, A.M.; Conti, F.; Di Leo, A.; Marzi, L.; Boccaccio, V.; Bollani, S.; Colombo, M. Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals. Dig. Liver Dis., 2019, 51(2), 310-317.
[http://dx.doi.org/10.1016/j.dld.2018.10.014] [PMID: 30473220]
[5]
Agapito, G.; Guzzi, P.; Cannataro, M. A parallel software pipeline for DMET microarray genotyping data analysis. High Throughput, 2018, 7(2), 17.
[http://dx.doi.org/10.3390/ht7020017] [PMID: 29904017]
[6]
Zhang, Z.; Xue, Y.; Zhao, F. Bioinformatics commons: The cornerstone of life and health sciences. Genomics Proteomics Bioinformatics, 2018, 16(4), 223-225.
[http://dx.doi.org/10.1016/j.gpb.2018.09.001] [PMID: 30268933]
[7]
Azofeifa, J.G.; Allen, M.A.; Lladser, M.E.; Dowell, R.D. An annotation agnostic algorithm for detecting nascent RNA transcripts in GRO-Seq. IEEE/ACM Trans. Comput. Biol. Bioinform, 2017, 14(5), 1070-1081.
[8]
Li, Y.; Zhu, Y.; Dai, G.; Wu, D.; Gao, Z.; Zhang, L.; Fan, Y. Screening and validating the core biomarkers in patients with pancreatic ductal adenocarcinoma. Math. Biosci. Eng., 2020, 17(1), 910-927.
[http://dx.doi.org/10.3934/mbe.2020048] [PMID: 31731384]
[9]
Lee, S.W.; Lee, H.Y.; Bang, H.J.; Song, H.J.; Kong, S.W.; Kim, Y.M. An improved prediction model for ovarian cancer using urinary biomarkers and a novel validation strategy. Int. J. Mol. Sci., 2019, 20(19), 4938.
[http://dx.doi.org/10.3390/ijms20194938] [PMID: 31590408]
[10]
Wang, B.; Lan, T.; Xiao, H.; Chen, Z.H.; Wei, C.; Chen, L.F.; Guan, J.F.; Yuan, R.F.; Yu, X.; Hu, Z.G.; Wu, H.J.; Dai, Z.; Wang, K. The expression profiles and prognostic values of HSP70s in hepatocellular carcinoma. Cancer Cell Int., 2021, 21(1), 286.
[http://dx.doi.org/10.1186/s12935-021-01987-9] [PMID: 34059060]
[11]
Zhou, Z.; Zhou, X.; Jiang, Y.; Qiu, M.; Liang, X.; Lin, Q.; Guo, Q.; Nong, C.; Huo, R.; Chen, Q.; Liu, H.; Liu, Y.; Zhu, S.; Wang, M.; Yu, H. Clinical significance of miR-1180-3p in hepatocellular carcinoma: A study based on bioinformatics analysis and RT-qPCR validation. Sci. Rep., 2020, 10(1), 11573.
[http://dx.doi.org/10.1038/s41598-020-68450-z] [PMID: 32665670]
[12]
Stefanska, B.; Huang, J.; Bhattacharyya, B.; Suderman, M.; Hallett, M.; Han, Z.G.; Szyf, M. Definition of the landscape of promoter DNA hypomethylation in liver cancer. Cancer Res., 2011, 71(17), 5891-5903.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-3823] [PMID: 21747116]
[13]
Zhang, H.; Ye, J.; Weng, X.; Liu, F.; He, L.; Zhou, D.; Liu, Y. Comparative transcriptome analysis reveals that the extracellular matrix receptor interaction contributes to the venous metastases of hepatocellular carcinoma. Cancer Genet., 2015, 208(10), 482-491.
[http://dx.doi.org/10.1016/j.cancergen.2015.06.002] [PMID: 26271415]
[14]
Itoh, S.; Maeda, T.; Shimada, M.; Aishima, S.; Shirabe, K.; Tanaka, S.; Maehara, Y. Role of expression of focal adhesion kinase in progression of hepatocellular carcinoma. Clin. Cancer Res., 2004, 10(8), 2812-2817.
[http://dx.doi.org/10.1158/1078-0432.CCR-1046-03] [PMID: 15102689]
[15]
Itoh, S.; Taketomi, A.; Tanaka, S.; Harimoto, N.; Yamashita, Y.; Aishima, S.; Maeda, T.; Shirabe, K.; Shimada, M.; Maehara, Y. Role of growth factor receptor bound protein 7 in hepatocellular carcinoma. Mol. Cancer Res., 2007, 5(7), 667-673.
[http://dx.doi.org/10.1158/1541-7786.MCR-06-0282] [PMID: 17634422]
[16]
Li, J. En, M.; Xing, H.; Zhang, Q.; Ma Zh, L.I.R.; Shen, C.; Tao, Y.; Wang, Z. Ncv index is a potential predictor of MVI in patients with HCC who undergoing liver transplantation. Transplantation, 2020, 104(Suppl. 3), S522.
[http://dx.doi.org/10.1097/01.tp.0000701320.47667.3b]
[17]
Heiat, M.; Negahdary, M. Sensitive diagnosis of alpha-fetoprotein by a label free nanoaptasensor designed by modified Au electrode with spindle-shaped gold nanostructure. Microchem. J., 2019, 148, 456-466.
[http://dx.doi.org/10.1016/j.microc.2019.05.004]
[18]
Song, W.S.; Park, H.G.; Ann, D.H.; Jeong, Y.Y.; Koo, M-Y.; Kim, Y-G. Quantitative analysis of core-fucosylated N-glycome according to serum AFP level for the diagnosis of hepatocellular carcinoma. Korean Soc. Biotechnol. Bioeng. J., 2017, 32(4), 279-285.
[http://dx.doi.org/10.7841/ksbbj.2017.32.4.279]
[19]
Semaan, A.; Dietrich, D.; Bergheim, D.; Dietrich, J.; Kalff, J.C.; Branchi, V.; Matthaei, H.; Kristiansen, G.; Fischer, H.P.; Goltz, D. CXCL12 expression and PD-L1 expression serve as prognostic biomarkers in HCC and are induced by hypoxia. Virchows Arch., 2017, 470(2), 185-196.
[http://dx.doi.org/10.1007/s00428-016-2051-5] [PMID: 27913861]
[20]
Nachmias, B.; Khan, D.H.; Voisin, V.; Mer, A.S.; Thomas, G.E.; Segev, N.; St-Germain, J.; Hurren, R.; Gronda, M.; Botham, A.; Wang, X.; Maclean, N.; Seneviratne, A.K.; Duong, N.; Xu, C.; Arruda, A.; Orouji, E.; Algouneh, A.; Hakem, R.; Shlush, L.; Minden, M.D.; Raught, B.; Bader, G.D.; Schimmer, A.D. IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells. Leukemia, 2022, 36(5), 1283-1295.
[http://dx.doi.org/10.1038/s41375-022-01513-4] [PMID: 35152270]
[21]
Cheng, D.D.; Li, S.J.; Zhu, B.; Yuan, T.; Yang, Q.C.; Fan, C.Y. Downregulation of BZW2 inhibits osteosarcoma cell growth by inactivating the Akt/mTOR signaling pathway. Oncol. Rep., 2017, 38(4), 2116-2122.
[http://dx.doi.org/10.3892/or.2017.5890] [PMID: 28791373]
[22]
Gao, H.; Yu, G.; Zhang, X.; Yu, S.; Sun, Y.; Li, Y. BZW2 gene knockdown induces cell growth inhibition, G1 arrest and apoptosis in muscle‐invasive bladder cancers: A microarray pathway analysis. J. Cell. Mol. Med., 2019, 23(6), 3905-3915.
[http://dx.doi.org/10.1111/jcmm.14266] [PMID: 30932331]
[23]
Liu, L.; Zhao, J.; Peng, Y.; Yang, M.; Zhang, L.; Jin, X. miR-let-7a-5p inhibits invasion and migration of hepatoma cells by regulating BZW2 expression. OncoTargets Ther., 2020, 13, 12269-12279.
[http://dx.doi.org/10.2147/OTT.S278954] [PMID: 33273832]
[24]
Jin, X.; Liao, M.; Zhang, L.; Yang, M.; Zhao, J. Role of the novel gene BZW2 in the development of hepatocellular carcinoma. J. Cell. Physiol., 2019, 234(9), 16592-16600.
[http://dx.doi.org/10.1002/jcp.28331] [PMID: 30805927]
[25]
Cheung, P.F.Y.; Yip, C.W.; Ng, L.W.C.; Lo, K.W.; Wong, N.; Choy, K.W.; Chow, C.; Chan, K.F.; Cheung, T.T.; Poon, R.T.P.; Fan, S.T.; Cheung, S.T. Establishment and characterization of a novel primary hepatocellular carcinoma cell line with metastatic ability in vivo. Cancer Cell Int., 2014, 14(1), 103.
[http://dx.doi.org/10.1186/s12935-014-0103-y] [PMID: 25349534]
[26]
Karavias, D.; Maroulis, I.; Papadaki, H.; Gogos, C.; Kakkos, S.; Karavias, D.; Bravou, V. Overexpression of CDT1 is a predictor of poor survival in patients with hepatocellular carcinoma. J. Gastrointest. Surg., 2016, 20(3), 568-579.
[http://dx.doi.org/10.1007/s11605-015-2960-7] [PMID: 26408331]
[27]
Cai, C.; Zhang, Y.; Hu, X.; Hu, W.; Yang, S.; Qiu, H.; Chu, T. CDT1 is a novel prognostic and predictive biomarkers for hepatocellular carcinoma. Front. Oncol., 2021, 11, 721644.
[http://dx.doi.org/10.3389/fonc.2021.721644] [PMID: 34631549]
[28]
Sakamoto, O.; Arai-Ichinoi, N.; Mitsubuchi, H.; Chinen, Y.; Haruna, H.; Maruyama, H.; Sugawara, H.; Kure, S. Phenotypic variability and newly identified mutations of the <i>IVD </i>gene in Japanese patients with isovaleric acidemia. Tohoku J. Exp. Med., 2015, 236(2), 103-106.
[http://dx.doi.org/10.1620/tjem.236.103] [PMID: 26018748]
[29]
Peljto, A.L.; Selman, M.; Kim, D.S.; Murphy, E.; Tucker, L.; Pardo, A.; Lee, J.S.; Ji, W.; Schwarz, M.I.; Yang, I.V.; Schwartz, D.A.; Fingerlin, T.E. The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries. Chest, 2015, 147(2), 460-464.
[http://dx.doi.org/10.1378/chest.14-0867] [PMID: 25275363]
[30]
Lu, B.; Yin, L.; Xu, L.; Peng, J. Application of proteomic and bioinformatic techniques for studying the hepatoprotective effect of dioscin against CCl₄-induced liver damage in mice. Planta Med., 2011, 77(5), 407-415.
[http://dx.doi.org/10.1055/s-0030-1250461] [PMID: 20979020]
[31]
Vockley, J.; Rogan, P.K.; Anderson, B.D.; Willard, J.; Seelan, R.S.; Smith, D.I.; Liu, W. Exon skipping in IVD RNA processing in isovaleric acidemia caused by point mutations in the coding region of the IVD gene. Am. J. Hum. Genet., 2000, 66(2), 356-367.
[http://dx.doi.org/10.1086/302751] [PMID: 10677295]
[32]
Lin, Y.; Chen, D.; Peng, W.; Wang, K.; Lin, W.; Zhuang, J.; Zheng, Z.; Li, M.; Fu, Q. Newborn screening for isovaleric acidemia in Quanzhou, China. Clin. Chim. Acta, 2020, 509, 25-29.
[http://dx.doi.org/10.1016/j.cca.2020.06.010] [PMID: 32505769]