NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP

Sakaguchi, Hiromi; Tsuchiya, Hiroyuki; Kitagawa, Yoshikazu; Tanino, Tadatoshi; Yoshida, Kenji; Uchida, Nobue; Shiota, Goshi

doi:10.3390/ijms23020711

Cited by 25 publications

(18 citation statements)

References 56 publications

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“…[57][58][59][60][61][62] Although the cancer cell lethality does not translate directly to better outcomes for patients, 56 our study implies the potential of BNCT for patients with advanced HCC. It is noteworthy that other mechanism related to radioresistance, such as autophagy, 63,64 may also involve in eliminating the radioresistant cells by BNCT. Therefore, further studies are still needed before its clinical application.…”

Section: Discussionmentioning

confidence: 99%

Boron Neutron Capture Therapy Eliminates Radioresistant Liver Cancer Cells by Targeting DNA Damage and Repair Responses

Huang

Lai

Hsu

et al. 2022

JHC

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Introduction:For advanced hepatocellular carcinoma (HCC), resistance to conservative treatments remains a challenge. In previous studies, the therapeutic effectiveness and DNA damage responses of boric acid-mediated boron neutron capture therapy (BA-BNCT) in HCC have been demonstrated in animal models and HCC cell line. On the other hand, numerous studies have shown that high linear energy transfer (LET) radiation can overcome tumor resistance. Since BNCT yields a mixture of high and low LET radiation, we aimed to explore whether and how BA-BNCT could eliminate radioresistant HCC cells. Methods: Radioresistant human HCC (HepG2-R) cells were established from HepG2 cells via intermittent irradiation. HepG2 and HepG2-R cells were then irradiated with either γ-ray or neutron radiation of BA-BNCT. Colony formation assays were used to assess cell survival and the relative biological effectiveness (RBE). The expression of phosphorylated H2AX (γH2AX) was also examined by immunocytochemistry and Western blot assays to evaluate the extent of DNA double-strand breaks (DSBs). Finally, the expression levels of DNA damage response-associated proteins were determined, followed by cell cycle analysis and caspase-3 activity analysis. Results: Our data demonstrated that under the same dose by γ-ray, BNCT effectively eliminated radioresistant HCC by increasing the number of DNA DSBs (p < 0.05) and impeding their repair (p < 0.05), which verified the high RBE of BNCT. We also found that BNCT resulted in delayed homologous recombination (HR) and inhibited the nonhomologous end-joining (NHEJ) pathway during DNA repair. Markedly, BNCT increased cell arrest (p < 0.05) in the G 2 /M phase by altering G 2 checkpoint signaling and increased PUMA-mediated apoptosis (p < 0.05). Conclusion: Our data suggest that DNA damage and repair responses could affect the anticancer efficiency of BNCT in radioresistant HepG2-R cells, which highlights the potential of BNCT as a viable treatment option for recurrent HCC.

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Section: Discussionmentioning

confidence: 99%

Boron Neutron Capture Therapy Eliminates Radioresistant Liver Cancer Cells by Targeting DNA Damage and Repair Responses

Huang

Lai

Hsu

et al. 2022

JHC

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“…The upregulation of NEAT1 in HCC has been associated with an important property known as radioresistance. This effect is mediated by overexpression of gamma-aminobutyric acid receptor-associated protein (GABARAP) and induction of autophagy [178]. The effect of autophagy on radioresistance in HCC is uncertain.…”

Section: Targeting Autophagy For Regulating Radioresistancementioning

confidence: 99%

Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches

et al. 2023

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Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Graphical abstract

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“…CSCs play a crucial role in drug resistance. Evidence has illustrated that NEAT1v1 promotes autophagy through gamma-aminobutyric acid receptor-associated protein, thereby conferring radioresistance to HCC cells ( 82 ).…”

Section: Mirnas Involved In the Regulation Of Autophagy In Hccmentioning

confidence: 99%

Non‑coding RNAs: Role of miRNAs and lncRNAs in the regulation of autophagy in hepatocellular carcinoma (Review)

et al. 2023

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The term autophagy describes a process that supports nutrient cycling and metabolic adaptation that is accomplished via multistep lysosomal degradation. These activities modulate cell, tissue and internal environment stability, and can also affect the occurrence and development of cancer. Previous studies have mostly described autophagy as having dual effects in cancer, serving to limit tumorigenesis in the early stages of cancer, but promoting tumor progression in certain types of cancer. There have been indications in recent years that microRNAs (miRNAs/miRs) and long non-coding RNAs (lncRNAs), as types of non-coding RNAs, play major roles in the occurrence, invasion, development and drug resistance of hepatocellular carcinoma (HCC) and in the migration of HCC cells by governing HCC cell autophagy. Therefore, understanding which miRNAs and lncRNAs play such roles and the relevant molecular mechanisms is critical. The present review highlights the significant functions of miRNAs and lncRNAs in the regulation of autophagy in HCC and the relevant mechanisms, aiming to provide novel insight into HCC therapeutics. Contents 1. Introduction 2. miRNAs involved in the regulation of autophagy in HCC 3. lncRNAs involved in the regulation of autophagy in HCC 4. Mechanisms of miRNAs and lncRNAs in the regulation of autophagy in HCC 5. Conclusions and future perspectives

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NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP

Cited by 25 publications

References 56 publications

Boron Neutron Capture Therapy Eliminates Radioresistant Liver Cancer Cells by Targeting DNA Damage and Repair Responses

Boron Neutron Capture Therapy Eliminates Radioresistant Liver Cancer Cells by Targeting DNA Damage and Repair Responses

Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches

Non‑coding RNAs: Role of miRNAs and lncRNAs in the regulation of autophagy in hepatocellular carcinoma (Review)

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