Interleukin-6-stimulated progranulin expression contributes to the malignancy of hepatocellular carcinoma cells by activating mTOR signaling

Liu, Feng; Zhang, Wen; Yang, Fusheng; Feng, Tingting; Zhou, Meng; Yu, Yuan; Yu, Xiuping; Zhao, Weiming; Yi, Fan; Tang, Wei; Lü, Yi

doi:10.1038/srep21260

Cited by 54 publications

(42 citation statements)

References 58 publications

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“…However, different types of growth factors and cytokines, such as SDF-1, HGF, epidermal growth factor (EGF), interleukin (IL)-6, and transforming growth factor (TGF)-β, implicated as autocrine and paracrine mediators of stromal-epithelial interactions are involved in tumor progression. 12,13,21,22 In this study, we observed that the CAFs secrete FGF-1 at a higher level than NFs. The function of FGF-1 was subsequently investigated in our study.…”

Section: Discussionmentioning

confidence: 50%

Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling

Sun

Fan²,

Zhang

et al. 2017

Tumour Biol.

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Ovarian cancer is the most lethal gynecologic malignancy, due to its high propensity for metastasis. Cancer-associated fibroblasts, as the dominant component of tumor microenvironment, are crucial for tumor progression. However, the mechanisms underlying the regulation of ovarian cancer cells by cancer-associated fibroblasts remain little known. Here, we first isolated cancer-associated fibroblasts from patients' ovarian tissues and found that cancer-associated fibroblasts promoted SKOV3 cells' proliferation, migration, and invasion. Fibroblast growth factor-1 was identified as a highly increased factor in cancer-associated fibroblasts compared with normal fibroblasts by quantitative reverse transcription polymerase chain reaction (~4.6-fold, p < 0.01) and ELISA assays (~4-fold, p < 0.01). High expression of fibroblast growth factor-1 in cancer-associated fibroblasts either naturally or through gene recombination led to phosphorylation of fibroblast growth factor receptor 4 in SKOV3 cells, which is followed by the activation of mitogenactivated protein kinase/extracellular signal-regulated protein kinase pathway and epithelial-to-mesenchymal transitionassociated gene Snail1 and MMP3 expression. Moreover, treatment of SKOV3 cell with fibroblast growth factor receptor inhibitor PD173074 terminated cellular proliferation, migration, and invasion, reduced the phosphorylation level of fibroblast growth factor receptor 4, and suppressed the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway. In addition, the expression level of Snail1 and MMP3 was reduced, while the expression level of E-cadherin increased. These observations suggest a crucial role for cancer-associated fibroblasts and fibroblast growth factor-1/fibroblast growth factor receptor 4 signaling in the progression of ovarian cancer. Therefore, this fibroblast growth factor-1/fibroblast growth factor receptor 4 axis may become a potential target for the treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 50%

Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling

Sun

Fan²,

Zhang

et al. 2017

Tumour Biol.

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“…The AKT and ERK signaling pathways have been commonly investigated downstream targets of PGRN in several types of tumor (23)(24)(25). ERK is also a crucial signal target, which is responsible for the expression of PGRN induced by interleukin-6 in hepatocellular carcinoma cells (20). In the present study, it was found that extracellular PGRN efficiently promoted the intracellular expression of PGRN via the AKT and ERK signaling pathways.…”

Section: Univariate Analysis Multivariate Analysis ------------------supporting

confidence: 55%

“…As a secretory protein, under the guidance of signaling peptides, PGRN is secreted to the outside of cells and can regulate intracellular gene expression through binding to corresponding receptors on cell membranes in an autocrine or paracrine manner. In 2016, Liu et al reported that rPGRN promoted the expression of Cyclin-B1 and Cyclin-D1 in HepG2 hepatocellular carcinoma cells, resulting in cell growth (20). In our previous study, PGRN was shown to promote the expression of Ki67 and vascular endothelial growth factor A in colorectal cancer cells (21).…”

Section: Univariate Analysis Multivariate Analysis ------------------mentioning

confidence: 89%

Clinical implications of progranulin in gastric cancer and its regulation via a positive feedback loop involving AKT and ERK signaling pathways

Yang¹,

Li²,

Wang³

et al. 2017

Molecular Medicine Reports

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In previous years, progranulin (PGRN) has attracted increasing attention due to its oncogenic roles in several types of tumor. However, the clinical relevance of PGRN in gastric cancer remains to be elucidated. In the present study, 120 retrospective tissue samples were obtained from patients with primary gastric cancer, and the expression of PGRN was detected using immunohistochemistry. The results showed that 71 cases exhibited a high expression of PGRN, which was markedly higher than the 49 cases with a low expression of PGRN. Subsequent χ2 analysis confirmed for the first time, to the best of our knowledge, that a high level of PGRN was positively correlated with lymph node metastasis (P=0.048), lymphatic invasion (P=0.018) and advanced clinical stage (P=0.027). Survival analysis showed that PGRN was positively correlated with poorer overall survival (OS; P=0.0043) and progression‑free survival (PFS; P=0.0022). Univariate and multivariate Cox regression analysis showed that PGRN and clinical stage had a significant effect on the OS and PFS of the patients with gastric cancer. In addition, cell experiments confirmed that extracellular PGRN promoted the intracellular expression of PGRN in a concentration‑dependent manner in gastric cancer cells. The AKT and extracellular signal‑regulated kinase signaling pathways were involved in the upregulation of intracellular PGRN induced by extracellular PGRN in MKN‑45 and MGC‑803 gastric cancer cells. Taken together, the results of the present study suggested that PGRN may be important in the progression and prognosis of gastric cancer, and that the expression of PGRN was regulated in a positive feedback loop. These findings enhance current knowledge regarding PGRN in tumors.

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“…To the best of our knowledge, this study is the first to demonstrate that PGRN is the functional target gene of miR‐34b‐5p. Interestingly, we also found the expression levels of miR‐34b‐5p and PGRN was both up‐regulated in the lungs from the mice with ALI at 24 hr, and we hypothesized that PGRN was not only regulated by miR‐34b‐5p but also modulated by various factors, such as TMEM106B and IL‐6 (Finch et al, ; Liu, Zhang, et al, ), indicating that other mechanisms may involve in the regulation of PGRN expression during ALI. We believe that elevated PGRN levels in the lungs are a comprehensive result of multiple factors, and the final seemingly positive correlation may mask its complicated mechanism.…”

Section: Discussionmentioning

confidence: 79%

miR‐34b‐5p inhibition attenuates lung inflammation and apoptosis in an LPS‐induced acute lung injury mouse model by targeting progranulin

Xie

Wang

et al. 2018

Journal Cellular Physiology

129

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Inflammation and apoptosis play important roles in the initiation and progression of acute lung injury (ALI). Our previous study has shown that progranulin (PGRN) exerts lung protective effects during LPS‐induced ALI. Here, we have investigated the potential roles of PGRN‐targeting microRNAs (miRNAs) in regulating inflammation and apoptosis in ALI and have highlighted the important role of PGRN. LPS‐induced lung injury and the protective roles of PGRN in ALI were first confirmed. The function of miR‐34b‐5p in ALI was determined by transfection of a miR‐34b‐5p mimic or inhibitor in intro and in vivo. The PGRN level gradually increased and subsequently significantly decreased, reaching its lowest value by 24 hr; PGRN was still elevated compared to the control. The change was accompanied by a release of inflammatory mediators and accumulation of inflammatory cells in the lungs. Using bioinformatics analysis and RT‐PCR, we demonstrated that, among 12 putative miRNAs, the kinetics of the miR‐34b‐5p levels were closely associated with PGRN expression in the lung homogenates. The gain‐ and loss‐of‐function analysis, dual‐luciferase reporter assays, and rescue experiments confirmed that PGRN was the functional target of miR‐34b‐5p. Intravenous injection of miR‐34b‐5p antagomir in vivo significantly inhibited miR‐34b‐5p up‐regulation, reduced inflammatory cytokine release, decreased alveolar epithelial cell apoptosis, attenuated lung inflammation, and improved survival by targeting PGRN during ALI. miR‐34b‐5p knockdown attenuates lung inflammation and apoptosis in an LPS‐induced ALI mouse model by targeting PGRN. This study shows that miR‐34b‐5p and PGRN may be potential targets for ALI treatments.

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Interleukin-6-stimulated progranulin expression contributes to the malignancy of hepatocellular carcinoma cells by activating mTOR signaling

Cited by 54 publications

References 58 publications

Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling

Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling

Clinical implications of progranulin in gastric cancer and its regulation via a positive feedback loop involving AKT and ERK signaling pathways

miR‐34b‐5p inhibition attenuates lung inflammation and apoptosis in an LPS‐induced acute lung injury mouse model by targeting progranulin

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