Inositol 1,4,5-trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia-reperfusion injury

Filho, Antônio Carlos Melo Lima; França, Andressa; Florentino, Rodrigo M.; Santos, Marcone Loiola dos; Lemos, Fernanda O.; Missiaggia, Dabny G.; Fonseca, Roberta Cristelli; Oliveira, André G.; Ananthanarayanan, Meenakshisundaram; Guerra, Mateus T.; Fonseca, Matheus de Castro; Vidigal, Paula Vieira Teixeira; Lima, Cristiano Xavier; Nathanson, Michael H.; Leite, M. Fátima

doi:10.1016/j.ceca.2020.102264

Cited by 3 publications

(6 citation statements)

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“…This is consistent with a previous finding that ITPR3 triggers anti-apoptotic gene expression in HCC cell lines (16). Similarities occur in colon cancer cells, in which ITPR3 overexpression is associated with decreased apoptosis (18) and in hepatocytes infected with yellow fever virus, in which higher ITPR3 hepatocyte expression prevents cell death through apoptosis (14).…”

Section: Discussionsupporting

confidence: 91%

“…For instance, under physiological conditions type 1 (ITPR1) and 2 (ITPR2) are the predominant isoforms in hepatocytes ( 10 , 11 ), while isoform 3 (ITPR3) is absent or minimally expressed ( 12 ). However, ITPR3 becomes significantly expressed in hepatocytes in acute ( 13 , 14 ) and chronic liver diseases, as well as in HCC and in liver cancer cell lines ( 15 , 16 ). ITPR3 expression is also increased in other malignancies, including cholangiocarcinoma ( 17 ), colon cancer ( 18 ), melanoma ( 19 ), mesothelioma and prostate cancer ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

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Inositol 1,4,5‑trisphosphate receptor type 3 is involved in resistance to apoptosis and maintenance of human hepatocellular carcinoma

et al. 2021

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The expression of the inositol 1,4,5-trisphosphate receptor type 3 (ITRP3) in hepatocytes is a common event in the pathogenesis of hepatocellular carcinoma (HCC), regardless of the type of underlying liver disease. However, it is not known whether ITPR3 expression in hepatocytes is involved in tumor maintenance. The aim of the present study was to determine whether there is an association between ITPR3 expression and clinical and morphological parameters using HCC samples obtained from liver explants from patients (n=53) with different etiologies of underlying chronic liver disease (CLD). ITPR3 expression, mitosis and apoptosis were analyzed in human liver samples by immunohistochemistry. Clinical and event-free survival data were combined to assess the relationship between ITPR3 and liver cancer growth in patients. RNA sequencing analysis was performed to identify apoptotic genes altered by ITPR3 expression in a liver tumor cell line. ITPR3 was highly expressed in HCC tumor cells relative to adjacent CLD tissue and healthy livers. There was an inverse correlation between ITPR3 expression and mitotic and apoptotic indices in HCC, suggesting that ITPR3 contributed to the maintenance of HCC by promoting resistance to apoptosis. This was confirmed by the upregulation of CTSB, CHOP and GADD45, genes involved in the apoptotic pathway in HCC. The expression of ITPR3 in the liver may be a promising prognostic marker of HCC

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Inositol 1,4,5‑trisphosphate receptor type 3 is involved in resistance to apoptosis and maintenance of human hepatocellular carcinoma

et al. 2021

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“…This intracellular calcium release channel is not expressed in hepatocytes under normal conditions, as previously shown by immunohistochemistry studies of histologically normal liver adjacent to resected colorectal cancer metastasis. ( 22 ) However, it becomes expressed in response to hepatocellular damage, both during acute types of liver injury such as ischemia‐reperfusion injury ( 18 ) and yellow fever infection, ( 17 ) and during chronic types of liver injury such as chronic viral hepatitis, alcohol‐associated liver disease, and nonalcoholic steatohepatitis. ( 22 ) Here, we found that each of 10 patients with COVID‐19 in whom this was examined had mild but consistent ITPR3 staining in their hepatocytes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In order to gain insight about the basis for the pathological findings, these have been correlated with liver tests. We also examined immunostaining for SARS-CoV-2, angiotensin converting enzyme 2 (ACE2), which is thought to be the point of entry of the virus into cells (16), and the type 3 inositol trisphosphate receptor (ITPR3), which increases in acute hepatocellular injury and may relate to the nature of the response to injury (17,18).…”

Section: Introductionmentioning

confidence: 99%

“…We also examined immunostaining for SARS-CoV-2, angiotensin converting enzyme 2 (ACE2), which is thought to be the point of entry of the virus into cells, (16) and the type 3 inositol trisphosphate receptor (ITPR3), which increases in acute hepatocellular injury and may relate to the nature of the response to injury. (17,18) Brazil, who were hospitalized between March 23 and May 18, 2020, after testing positive for SARs-CoV-2 through quantitative real-time polymerase chain reaction (PCR). Liver specimens of approximately 1 cm 3 were obtained from multiple sites during necropsy and fixed in neutral buffered formalin and embedded in paraffin.…”

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Correlation Between Clinical and Pathological Findings of Liver Injury in 27 Patients With Lethal COVID‐19 Infections in Brazil

et al. 2021

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Liver test abnormalities are frequently observed in COVID-19 patients and are associated with worse prognosis. However, information is limited about pathological changes in the liver in this infection, so the mechanism of liver injury is unclear. Here we describe liver histopathology and clinical correlates of 27 patients who died of COVID-19 in Manaus, Brazil. There was a high prevalence of liver injury (elevated ALT and AST in 44% and 48% of patients, respectively) in these patients. Histological analysis showed sinusoidal congestion and ischemic necrosis in more than 85% of the cases, but these appeared to be secondary to systemic rather than intrahepatic thrombotic events, as only 14% and 22% of samples were positive for CD61 (marker of platelet activation) and C4d (activated complement factor), respectively. Furthermore, the extent of these vascular findings did not correlate with the extent of transaminase elevations. Steatosis was present in 63% of patients, and portal inflammation was present in 52%. In most cases hepatocytes expressed angiotensin converting enzyme 2 (ACE2), which is responsible for binding and entry of SARS-CoV-2, even though this ectoenzyme was minimally expressed on hepatocytes in normal controls. However, SARS-CoV-2 staining was not observed. Most hepatocytes also expressed ITPR3, a calcium channel that becomes expressed in acute liver injury. Conclusion: The hepatocellular injury that commonly occurs in patients with severe COVID-19 is not due to the vascular events that contribute to pulmonary or cardiac damage. However, new expression of ACE2 and ITPR3 with concomitant inflammation and steatosis suggests that liver injury may result from inflammation, metabolic abnormalities and perhaps direct viral injury.

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Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype

Gong,

Ogino,

Leite

et al. 2023

Preprint

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Liver cancer involves tumor cells rapidly growing within a packed tissue environment. Patient tumor tissues reveal densely packed and deformed cells, especially at tumor boundaries, indicative of physical crowding and compression. It is not well understood how these physical signals modulate tumor evolution and therapeutic susceptibility. Here we investigate the impact of volumetric compression on liver cancer (HepG2) behavior. We find that conditioning cells under a highly compressed state leads to major transcriptional reprogramming, notably the loss of hepatic markers, the epithelial-to-mesenchymal transition (EMT)-like changes, and altered calcium signaling-related gene expression, over the course of several days. Biophysically, compressed cells exhibit increased Rac1-mediated cell spreading and cell-extracellular matrix interactions, cytoskeletal reorganization, increased YAP and β-catenin nuclear translocation, and dysfunction in cytoplasmic and mitochondrial calcium signaling. Furthermore, compressed cells are resistant to chemotherapeutics and desensitized to apoptosis signaling. Apoptosis sensitivity can be rescued by stimulated calcium signaling. Our study demonstrates that volumetric compression is a key microenvironmental factor that drives tumor evolution in multiple pathological directions and highlights potential countermeasures to re-sensitize therapy-resistant cells.Significance statementCompression can arise as cancer cells grow and navigate within the dense solid tumor microenvironment. It is unclear how compression mediates critical programs that drive tumor progression and therapeutic complications. Here, we take an integrative approach in investigating the impact of compression on liver cancer. We identify and characterize compressed subdomains within patient tumor tissues. Furthermore, using in vitro systems, we induce volumetric compression (primarily via osmotic pressure but also via mechanical force) on liver cancer cells and demonstrate significant molecular and biophysical changes in cell states, including in function, cytoskeletal signaling, proliferation, invasion, and chemoresistance. Importantly, our results show that compressed cells have impaired calcium signaling and acquire resistance to apoptosis, which can be countered via calcium mobilization.

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Inositol 1,4,5-trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia-reperfusion injury

Cited by 3 publications

References 52 publications

Inositol 1,4,5‑trisphosphate receptor type 3 is involved in resistance to apoptosis and maintenance of human hepatocellular carcinoma

Inositol 1,4,5‑trisphosphate receptor type 3 is involved in resistance to apoptosis and maintenance of human hepatocellular carcinoma

Correlation Between Clinical and Pathological Findings of Liver Injury in 27 Patients With Lethal COVID‐19 Infections in Brazil

Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype

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