Skip to main content
Erschienen in: Digestive Diseases and Sciences 10/2021

27.11.2020 | Original Article

HIPK3 Circular RNA Promotes Metastases of HCC Through Sponging miR-338-3p to Induce ZEB2 Expression

verfasst von: Weizhi Li, Hui Xue, Yingchao Li, Peijie Li, Fuquan Ma, Mengying Liu, Shuzhen Kong

Erschienen in: Digestive Diseases and Sciences | Ausgabe 10/2021

Einloggen, um Zugang zu erhalten

Abstract

Background

Upregulation of circHIPK3 has been observed in several kinds of malignancies. However, the mechanisms of circHIPK3 in HCC metastases remains unclear. We investigated the role and the mechanisms of circHIPK3 in the development of HCC.

Methods

HCC tissues and paired adjacent non-tumor tissues of surgical patients were used to evaluate circHIPK3 expression. A series of biological experiments had been taken to evaluate the pro-metastatic ability of circHIPK3 during HCC development in vitro and in vivo. The potential mechanisms of circHIPK3 in HCC development were identified by RT-qPCR, Western blot, RIP, and luciferase reporter assays.

Results

CircHIPK3 expression is significantly upregulated during HCC development. Overexpression of circHIPK3 promotes cell migration, invasion, and metastases in vitro and in vivo. CircHIPK3 promoted HCC metastases by sponging miR-338-3p to regulate EMT-associated proteins E-cadherin, vimentin, and ZEB2 expression.

Conclusion

CircHIPK3 plays a regulatory role in metastatic HCC by sponging miR-338-3p to induce ZEB2 expression, thus promoting EMT procession.
Literatur
1.
Zurück zum Zitat Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRef Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRef
2.
Zurück zum Zitat Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.CrossRef Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.CrossRef
3.
Zurück zum Zitat Chang RM, Xiao S, Lei X, et al. miRNA-487a Promotes proliferation and metastasis in hepatocellular carcinoma. Clin Cancer Res. 2017;23:2593–2604.CrossRef Chang RM, Xiao S, Lei X, et al. miRNA-487a Promotes proliferation and metastasis in hepatocellular carcinoma. Clin Cancer Res. 2017;23:2593–2604.CrossRef
4.
Zurück zum Zitat Yang LY, Fang F, Ou DP, et al. Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection. Ann Surg. 2009;249:118–123.CrossRef Yang LY, Fang F, Ou DP, et al. Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection. Ann Surg. 2009;249:118–123.CrossRef
5.
Zurück zum Zitat Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013;342:1234850.CrossRef Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013;342:1234850.CrossRef
6.
Zurück zum Zitat Li Y, Zheng Q, Bao C, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25:981–984.CrossRef Li Y, Zheng Q, Bao C, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25:981–984.CrossRef
7.
Zurück zum Zitat Zheng Q, Bao C, Guo W, et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun. 2016;7:11215.CrossRef Zheng Q, Bao C, Guo W, et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun. 2016;7:11215.CrossRef
8.
Zurück zum Zitat Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–338.CrossRef Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–338.CrossRef
9.
Zurück zum Zitat Guo JU, Agarwal V, Guo H, et al. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014;15:409.CrossRef Guo JU, Agarwal V, Guo H, et al. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014;15:409.CrossRef
10.
Zurück zum Zitat Conn SJ, Pillman KA, Toubia J, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell. 2015;160:1125–1134.CrossRef Conn SJ, Pillman KA, Toubia J, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell. 2015;160:1125–1134.CrossRef
11.
Zurück zum Zitat He C, Huang C, Zhou R, et al. CircLMNB1 promotes colorectal cancer by regulating cell proliferation, apoptosis and epithelial-mesenchymal transition. Onco Targets Ther. 2019;12:6349–6359.CrossRef He C, Huang C, Zhou R, et al. CircLMNB1 promotes colorectal cancer by regulating cell proliferation, apoptosis and epithelial-mesenchymal transition. Onco Targets Ther. 2019;12:6349–6359.CrossRef
12.
Zurück zum Zitat Zhang X, Wang S, Wang H, et al. Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. 2019;18:20. Zhang X, Wang S, Wang H, et al. Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. 2019;18:20.
13.
Zurück zum Zitat Cao R, Shao J, Hu Y, et al. MicroRNA-338-3p inhibits proliferation, migration, invasion, and EMT in osteosarcoma cells by targeting activator of 90 kDa heat shock protein ATPase homolog 1. Cancer Cell Int. 2018;18:49.CrossRef Cao R, Shao J, Hu Y, et al. MicroRNA-338-3p inhibits proliferation, migration, invasion, and EMT in osteosarcoma cells by targeting activator of 90 kDa heat shock protein ATPase homolog 1. Cancer Cell Int. 2018;18:49.CrossRef
14.
Zurück zum Zitat Chen JS, Liang LL, Xu HX, et al. miR-338-3p inhibits epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma cells. Oncotarget. 2017;8:71418–71429.CrossRef Chen JS, Liang LL, Xu HX, et al. miR-338-3p inhibits epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma cells. Oncotarget. 2017;8:71418–71429.CrossRef
15.
Zurück zum Zitat Li Y, Chen P, Zu L, et al. MicroRNA-338-3p suppresses metastasis of lung cancer cells by targeting the EMT regulator Sox4. Am J Cancer Res. 2016;6:127–140.PubMedPubMedCentral Li Y, Chen P, Zu L, et al. MicroRNA-338-3p suppresses metastasis of lung cancer cells by targeting the EMT regulator Sox4. Am J Cancer Res. 2016;6:127–140.PubMedPubMedCentral
16.
Zurück zum Zitat Huang N, Wu Z, Lin L, et al. MiR-338-3p inhibits epithelial-mesenchymal transition in gastric cancer cells by targeting ZEB2 and MACC1/Met/Akt signaling. Oncotarget. 2015;6:15222–15234.CrossRef Huang N, Wu Z, Lin L, et al. MiR-338-3p inhibits epithelial-mesenchymal transition in gastric cancer cells by targeting ZEB2 and MACC1/Met/Akt signaling. Oncotarget. 2015;6:15222–15234.CrossRef
17.
Zurück zum Zitat Xia L, Huang W, Tian D, et al. Forkhead box Q1 promotes hepatocellular carcinoma metastasis by transactivating ZEB2 and VersicanV1 expression. Hepatology. 2014;59:958–973.CrossRef Xia L, Huang W, Tian D, et al. Forkhead box Q1 promotes hepatocellular carcinoma metastasis by transactivating ZEB2 and VersicanV1 expression. Hepatology. 2014;59:958–973.CrossRef
18.
Zurück zum Zitat Yuan JH, Yang F, Wang F, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666–681.CrossRef Yuan JH, Yang F, Wang F, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666–681.CrossRef
19.
Zurück zum Zitat Liu N, Zhang J, Zhang LY, et al. CircHIPK3 is upregulated and predicts a poor prognosis in epithelial ovarian cancer. Eur Rev Med Pharmacol Sci. 2018;22:3713–3718.PubMed Liu N, Zhang J, Zhang LY, et al. CircHIPK3 is upregulated and predicts a poor prognosis in epithelial ovarian cancer. Eur Rev Med Pharmacol Sci. 2018;22:3713–3718.PubMed
20.
Zurück zum Zitat Cai C, Zhi Y, Wang K, et al. CircHIPK3 overexpression accelerates the proliferation and invasion of prostate cancer cells through regulating miRNA-338-3p. Onco Targets Ther. 2019;12:3363–3372.CrossRef Cai C, Zhi Y, Wang K, et al. CircHIPK3 overexpression accelerates the proliferation and invasion of prostate cancer cells through regulating miRNA-338-3p. Onco Targets Ther. 2019;12:3363–3372.CrossRef
22.
Zurück zum Zitat Chen X, Mao R, Su W, et al. Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKalpha signaling in STK11 mutant lung cancer. 2019:1–13. Chen X, Mao R, Su W, et al. Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKalpha signaling in STK11 mutant lung cancer. 2019:1–13.
23.
Zurück zum Zitat Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454.CrossRef Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454.CrossRef
24.
Zurück zum Zitat Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–890.CrossRef Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–890.CrossRef
25.
Zurück zum Zitat Vleminckx K, Vakaet L Jr, Mareel M, et al. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 1991;66:107–119.CrossRef Vleminckx K, Vakaet L Jr, Mareel M, et al. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 1991;66:107–119.CrossRef
26.
Zurück zum Zitat Vuoriluoto K, Haugen H, Kiviluoto S, et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 2011;30:1436–1448.CrossRef Vuoriluoto K, Haugen H, Kiviluoto S, et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 2011;30:1436–1448.CrossRef
27.
Zurück zum Zitat Hong-Yuan W, Xiao-Ping C. miR-338-3p suppresses epithelial-mesenchymal transition and metastasis in human nonsmall cell lung cancer. Indian J Cancer. 2015;52:E168–E171.CrossRef Hong-Yuan W, Xiao-Ping C. miR-338-3p suppresses epithelial-mesenchymal transition and metastasis in human nonsmall cell lung cancer. Indian J Cancer. 2015;52:E168–E171.CrossRef
28.
Zurück zum Zitat Peinado H, Portillo F, Cano A. Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol. 2004;48:365–375.CrossRef Peinado H, Portillo F, Cano A. Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol. 2004;48:365–375.CrossRef
Metadaten
Titel
HIPK3 Circular RNA Promotes Metastases of HCC Through Sponging miR-338-3p to Induce ZEB2 Expression
verfasst von
Weizhi Li
Hui Xue
Yingchao Li
Peijie Li
Fuquan Ma
Mengying Liu
Shuzhen Kong
Publikationsdatum
27.11.2020
Verlag
Springer US
Erschienen in
Digestive Diseases and Sciences / Ausgabe 10/2021
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-020-06688-3

Weitere Artikel der Ausgabe 10/2021

Digestive Diseases and Sciences 10/2021 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.