Inositol 1, 4, 5-trisphosphate-dependent nuclear calcium signals regulate angiogenesis and cell motility in triple negative breast cancer

Background & objectivesHepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca2+ signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca2+ release channels in HCC.DesignExpression analyses of the type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR3) in human liver samples, liver cancer cells and mouse liver were combined with an evaluation of DNA methylation profiles of ITPR3 promoter in HCC and characterisation of the effects of ITPR3 expression on cellular proliferation and apoptosis. The effects of de novo ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice.ResultsITPR3 was absent or expressed in low amounts in hepatocytes from normal liver, but was expressed in HCC specimens from three independent patient cohorts, regardless of the underlying cause of chronic liver disease, and its increased expression level was associated with poorer survival. The ITPR3 gene was heavily methylated in control liver specimens but was demethylated at multiple sites in specimens of patient with HCC. Administration of a demethylating agent in a mouse model resulted in ITPR3 expression in discrete areas of the liver, and Ca2+ signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of ITPR3 from human HCC cells enhanced apoptosis.ConclusionsThese results provide evidence that de novo expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis.

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“…Western blots of hepatocyte and liver cancer cell lysates were performed as previously described. 16…”

Section: Immunoblottingmentioning

confidence: 99%

Expression of the type 3 InsP₃receptor is a final common event in the development of hepatocellular carcinoma

Guerra

Florentino

França

et al. 2019

Gut

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“…It was reported that ERα suppresses the movement of BC cells by up-regulating VCL [ 27 ]. In another study, nuclear calcium buffering regulates BC cell motility, likely due to enhanced VCL expression [ 28 ]. The analysis also showed other potential targets of miR-200b-3p regulating CDK family members, such as SP1 and E2F3.…”

Section: Resultsmentioning

confidence: 99%

The microRNAs miR-200b-3p and miR-429-5p target the LIMK1/CFL1 pathway to inhibit growth and motility of breast cancer cells

Wang

Song

et al. 2017

Oncotarget

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Triple-negative breast cancer (TNBC) has the worst prognosis of all subtypes of breast cancer (BC), with limited options for conventional therapy and no targeted therapies. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. In this study, we aimed to determine whether two members of the miR-200 family, miR-200b-3p and miR-429-5p, are involved in BC cell proliferation and motility and to elucidate their target genes and pathways. We performed a meta-analysis that reveals down-regulated expression of miR-200b-3p and miR-429-5p in BC tissues and cell lines, consistent with a lower expression of miR-200b-3p and miR-429-5p in MDA-MB-231 and HCC1937 cells than in MCF-7 and MCF-10 cells. Overexpression of miR-200b-3p and miR-429-5p significantly inhibited the proliferation, migration, and invasion of TNBC cells; suppressed the expression of markers for proliferation and metastasis in TNBC cells. We next demonstrated that LIM domain kinase 1 (LIMK1) is a direct target gene of miR-200b-3p and miR-429-5p. Inhibition of LIMK1 reduced the expression and phosphorylation of cofilin 1 (CFL1), which polymerizes and depolymerizes F-actin and G-actin to reorganize cellular actin cytoskeleton. In addition, transfection with mimics for miR-200b-3p and miR-429-5p arrested G2/M and G0/G1 cell cycles respectively, suppressed the expression of the cell cycle–related complexes, cyclin D1/CDK4/CDK6 and cyclin E1/CDK2, in TNBC cells. In conclusion, miR-200b-3p and miR-429-5p suppress proliferation, migration, and invasion in TNBC cells, via the LIMK1/CFL1 pathway. These results provide insight into how specific miRNAs regulate TNBC progression and suggest that the LIMK1/CFL1 pathway is a therapeutic target for treating TNBC.

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“…Calcium (Ca 2+ ) is known to regulate several important cell functions, such as secretion, proliferation, apoptosis, protein biosynthesis and folding (Alvarenga et al, 2016; Carafoli & Krebs, 2016; Fonseca et al, 2018; Guimaraes et al, 2017). In order to study the effects of A. muciniphila conditioned media in the fluctuations of intracellular Ca 2+ signaling in STC-1 cells, we first stimulated Fluo-4/AM-loaded cells with 1 or 10% conditioned BHI medium (BHI CM) or unconditioned BHI medium (BHI).…”

Section: Resultsmentioning

confidence: 99%

Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cells

Jvp

et al. 2021

Preprint

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The notion that the gut microbiota play a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson's disease (PD) fecal samples. Nevertheless, a functional link between A.muciniphila and sporadic PD remained unexplored. Here, we investigated whether A.muciniphila secretome could initiate the misfolding process of α-synuclein (αSyn) in enteroendocrine cells (EECs), which are part of the gut epithelium and possess many neuron-like properties. We found that A.muciniphila secretome is directly modulated by mucin, induces intracellular calcium (Ca2+) release, and causes increased mitochondrial Ca2+ uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and αSyn aggregation. However, these events were efficiently inhibited once we buffered mitochondrial Ca2+. Thereby, these molecular insights provided here offer evidence that bacterial secretome is capable of inducing αSyn aggregation in enteroendocrine cells.

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Inositol 1, 4, 5-trisphosphate-dependent nuclear calcium signals regulate angiogenesis and cell motility in triple negative breast cancer

Cited by 16 publications

References 52 publications

Expression of the type 3 InsP₃receptor is a final common event in the development of hepatocellular carcinoma

Expression of the type 3 InsP₃receptor is a final common event in the development of hepatocellular carcinoma

The microRNAs miR-200b-3p and miR-429-5p target the LIMK1/CFL1 pathway to inhibit growth and motility of breast cancer cells

Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cells

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Inositol 1, 4, 5-trisphosphate-dependent nuclear calcium signals regulate angiogenesis and cell motility in triple negative breast cancer

Cited by 16 publications

References 52 publications

Expression of the type 3 InsP3receptor is a final common event in the development of hepatocellular carcinoma

Expression of the type 3 InsP3receptor is a final common event in the development of hepatocellular carcinoma

The microRNAs miR-200b-3p and miR-429-5p target the LIMK1/CFL1 pathway to inhibit growth and motility of breast cancer cells

Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cells

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Expression of the type 3 InsP₃receptor is a final common event in the development of hepatocellular carcinoma

Expression of the type 3 InsP₃receptor is a final common event in the development of hepatocellular carcinoma