Protein kinase D2 contributes to TNF-α-induced epithelial mesenchymal transition and invasion<i>via</i>the PI3K/GSK-3β/β-catenin pathway in hepatocellular carcinoma

Zhu, Yun; Cheng, Yang; Guo, Yabin; Chen, JinZhang; Chen, FengSheng; Luo, Rong; Li, Aimin

doi:10.18632/oncotarget.6633

Cited by 43 publications

(31 citation statements)

References 40 publications

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“…These patients also do not suffer from liver dysfunction (Hogan et al, 2015). Likewise, PKD1 mutations are rarely observed in HCC or cholangiocarcinoma, and there is evidence that PKD2 overexpression is oncogenic in HCC (Zhu et al, 2016). We showed that Pkd1 heterozygosity resulted in reduced hepatocyte death and fibrosis after injury, raising the possibility that these mutations could make the microenvironment less cancer-prone.…”

Section: Discussionmentioning

confidence: 72%

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease

Zhu

Jia

et al. 2019

Cell

200

153

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Section: Discussionmentioning

confidence: 72%

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease

Zhu

Jia

et al. 2019

Cell

200

153

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“…Triggers of EMT in HCC. Schematic representation of molecular pathways triggering EMT in HCC development and progression[105,[109][110][111][112][113][114][115].…”

mentioning

confidence: 99%

Role of epithelial to mesenchymal transition in hepatocellular carcinoma

Giannelli

Koudelková

Dituri

et al. 2016

Journal of Hepatology

505

394

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The epithelial to mesenchymal transition (EMT) is a multistep biological process whereby epithelial cells change in plasticity by transient de-differentiation into a mesenchymal phenotype. EMT and its reversal, mesenchymal to epithelial transition (MET), essentially occur during embryogenetic morphogenesis and have been increasingly described in fibrosis and cancer during the last decade. In carcinoma progression, EMT plays a crucial role in early steps of metastasis when cells lose cell-cell contacts due to ablation of E-cadherin and acquire increased motility to spread into surrounding or distant tissues. Epithelial plasticity has become a hot issue in hepatocellular carcinoma (HCC), as strong inducers of EMT such as transforming growth factor-β are able to orchestrate both fibrogenesis and carcinogenesis, showing rising cytokine levels in cirrhosis and late stage HCC. In this review, we consider the significance of EMT-MET in malignant hepatocytes as well as changes in the plasticity of hepatic stellate cells for cellular heterogeneity of HCC, and further aim at explaining the current limiting insights into EMT by snapshot analyses of HCC tissues. Recent advances in the identification of clinically relevant mechanisms that impinge on important EMT-transcription factors, as well as on miRNAs causing EMT signatures and HCC progression are highlighted. In addition, we draw particular attention to framing EMT in the context of potential clinical relevance for HCC patients. We conclude that some aspects of EMT are still elusive and further studies are required to better link the clinical management of HCC with biomarkers and targeted therapies related to EMT.

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“…Various systems have been utilized to induce eMT in human Hcc cell lines (33,34). Stimulation of Hcc cells with TnF-α leads to the induction of eMT (35). TnF-α is known to induce eMT alone or in combination with other cytokines such as transforming growth factor (TGF)-β in several cancer types, such as breast cancer, lung cancer and Hcc (19,21,25).…”

Section: Discussionmentioning

confidence: 99%

TNF‑α‑mediated epithelial‑to‑mesenchymal transition regulates expression of immune checkpoint molecules in hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (Hcc) is the fastest growing cause of cancer-related deaths globally. epithelial-to-mesenchymal transition (eMT) is a cellular process that confers Hcc tumor cells with the ability to evade the immune system. immune escape in most tumors, including Hcc, is controlled by immune checkpoint molecules. The aim of the present study was to investigate the association between eMT and immune checkpoint in Hcc, and identify novel therapeutic targets for Hcc. an in vitro model of reversible eMT was utilized based on cytokine tumor necrosis factor (TnF)-α treatment of Hcc cell lines Hep3B and Plc/PrF/5. Hep3B and Plc/PrF/5 cells were treated with TnF-α, and the eMT status and the expression of immune checkpoint molecules was assessed by reverse transcription-quantitative Pcr, western blotting and immunofluorescence. To confirm an association between eMT and immune modulators, cells were exposed to culture medium with TnF-α for 3 days to induce eMT, following which a reversal assay was performed. The expression of immune modulators and mesenchymal-to-epithelial transition (MeT) status was investigated upon reversal of eMT. Furthermore, Survexpress, a web-based platform was utilized to analyze survival and recurrence in a dataset of patients with Hcc. TnF-α treatment for 3 days induced eMT in Hep3B and Plc/PrF/5 cells, as demonstrated by the downregulation of epithelial markers along with upregulation in mesenchymal markers. an eMT reversal assay was able to induce MeT by increasing epithelial markers and decreasing mesenchymal markers. TnF-α-induced eMT led to the upregulation of immune modulators, including programmed death receptor ligand (PD-L)1, PD-L2, CD73 and B7-H3. in contrast, reversal of eMT suppressed the expression of PD-L1, PD-L2, CD73 and B7-H3. in addition, high expression of TnF-α and Pd-l1 in 422 patients with Hcc was associated with poor overall survival. The coordinate expression of TnF-α with Pd-l2 in this patient cohort was associated with increased Hcc recurrence. in conclusion, the present study demonstrated a close association between immune modulator expression and eMT induction/reversal driven by TnF-α.

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Protein kinase D2 contributes to TNF-α-induced epithelial mesenchymal transition and invasionviathe PI3K/GSK-3β/β-catenin pathway in hepatocellular carcinoma

Cited by 43 publications

References 40 publications

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease

Role of epithelial to mesenchymal transition in hepatocellular carcinoma

TNF‑α‑mediated epithelial‑to‑mesenchymal transition regulates expression of immune checkpoint molecules in hepatocellular carcinoma

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