Inhibitory effects of LOXL2 knockdown on cellular functions of liver cancer stem cells

Li, Na; Gu, Hui; Liu, Liu; Zhang, Xiaoli; Cheng, Qiu-Luo; Zhu, Ying

doi:10.21037/tcr-22-298

Cited by 6 publications

(4 citation statements)

References 41 publications

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“…Inhibition of LOXL2 follows the onset of liver brosis and augments collagen degradation [47], which in uences tissue stiffness and resilience [48]. In addition, knockdown of LOXL2 induced apoptosis and cell cycle arrest in liver cancer stem cells [49]. Assessment of the barrier function in addition to immunostaining con rmed the presence of these toxic events in our organoid model.…”

Section: Discussionmentioning

confidence: 71%

Cholangiocyte Organoids to Model Chlorpromazine-Induced Bile Duct Injury

Wang,

Xing,

Laan

et al. 2023

Preprint

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Background Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. Methods Here, we investigated the mechanisms of chlorpromazine(CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. Results CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. Conclusion These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.

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Section: Discussionmentioning

confidence: 71%

Cholangiocyte Organoids to Model Chlorpromazine-Induced Bile Duct Injury

Wang,

Xing,

Laan

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Inhibition of LOXL2 follows the onset of liver fibrosis and augments collagen degradation [ 48 ], which influences tissue stiffness and resilience [ 49 ]. In addition, knockdown of LOXL2 induced apoptosis and cell cycle arrest in liver cancer stem cells [ 50 ]. These results indicated that CPZ may lead to barrier disruption of the cholangiocytes, regardless of the cholestatic or non-cholestatic condition.…”

Section: Discussionmentioning

confidence: 99%

Cholangiocyte organoids to study drug-induced injury

Wang,

Xing,

van der Laan

et al. 2024

Stem Cell Res Ther

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Background Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. Methods Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. Results CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. Conclusion These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.

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“…A better understanding of LOXL2-mediated vasculogenic mimicry may enable the development of a new treatment strategy, which could compensate for the side effects of classical antiangiogenic drugs used in HCC treatment. In the study by Li et al, from 2022, the authors demonstrated that the knockdown of LOXL2 effectively inhibited the expression of the anti-apoptosis proteins BIRC3 and MDM2 and induced cell apoptosis and cell cycle arrest in HCC cell lines [135]. However, further research is needed to fully understand the complexities of the LOXL2-mediated apoptosis pathways and their implications in HCC [29,67,[123][124][125][126][127][128][129][130][131][132][133][134][135].…”

Section: Loxl2 and Hypoxia Angiogenesis And Vasculogenic Mimicrymentioning

confidence: 99%

Multiple Roles of LOXL2 in the Progression of Hepatocellular Carcinoma and Its Potential for Therapeutic Targeting

Radic

Kožik

Nikolić

et al. 2023

IJMS

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LOXL2, a copper-dependent amine oxidase, has emerged as a promising therapeutic target in hepatocellular carcinoma (HCC). Increased LOXL2 expression in HCC has been linked with an aggressive phenotype and represents a poor prognostic factor. Here, we focus on the mechanisms through which LOXL2 orchestrates multiple oncogenic functions in HCC development. We performed a review of the current knowledge on the roles LOXL2 performs in the modulation of the HCC tumor microenvironment, formation of premetastatic niches, and epithelial–mesenchymal transition. We also highlighted the complex interplay between LOXL2 and hypoxia, angiogenesis, and vasculogenic mimicry in HCC. At the end of the review, we summarize the current LOXL2 inhibitors and discuss their potential in HCC precision treatment.

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Inhibitory effects of LOXL2 knockdown on cellular functions of liver cancer stem cells

Cited by 6 publications

References 41 publications

Cholangiocyte Organoids to Model Chlorpromazine-Induced Bile Duct Injury

Cholangiocyte Organoids to Model Chlorpromazine-Induced Bile Duct Injury

Cholangiocyte organoids to study drug-induced injury

Multiple Roles of LOXL2 in the Progression of Hepatocellular Carcinoma and Its Potential for Therapeutic Targeting

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