Transforming growth factor-beta1 suppresses hepatocellular carcinoma proliferation via activation of Hippo signaling

Zhang, Xiaodong; Fan, Qing; Li, Yan; Yang, Zhaoguo; Yang, Liang; Zong, Zhi‐Hong; Wang, Biao; Meng, Xin; Li, Qin; Liu, Jingang; Li, Hangyu

doi:10.18632/oncotarget.14523

Cited by 25 publications

(20 citation statements)

References 29 publications

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“…Additionally, reduced TβRII staining has been observed in approximately 25% of malignant compared to adjacent nonmalignant hepatocytes [91]. TGF-β was also found to suppress HCC proliferation through activating Hippo signaling [92]. NADPH oxidase 4 may mediate the antiproliferative and proapoptotic effects of TGF-β in HCC cells [93].…”

Section: Role Of Tgf-β Signal In Gastrointestinal Cancersmentioning

confidence: 99%

The Role of TGF-β and Its Receptors in Gastrointestinal Cancers

Luo

Chen

2019

Translational Oncology

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Early detection of gastrointestinal tumors improves patient survival. However, patients with these tumors are typically diagnosed at an advanced stage and have poor prognosis. The incidence and mortality of gastrointestinal cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers, are increasing worldwide. Novel diagnostic and therapeutic agents are required to improve patient survival and quality of life. The tumor microenvironment, which contains nontumor cells, signaling molecules such as growth factors and cytokines, and extracellular matrix proteins, plays a critical role in cancer cell proliferation, invasion, and metastasis. Transforming growth factor beta (TGF-β) signaling has dual roles in gastrointestinal tumor development and progression as both a tumor suppressor and tumor promoter. Here, we review the dynamic roles of TGF-β and its receptors in gastrointestinal tumors and provide evidence that targeting TGF-β signaling may be an effective therapeutic strategy.

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Section: Role Of Tgf-β Signal In Gastrointestinal Cancersmentioning

confidence: 99%

The Role of TGF-β and Its Receptors in Gastrointestinal Cancers

Luo

Chen

2019

Translational Oncology

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“…Zhang et al found that TGF-β-induced expression of large tumor suppressor 1 (LATS1) and nucleus-cytoplasm translocation of yes association protein 1 (YAP1) resulted in cell growth inhibition in HCC cells. 45 Chen et al screened almost 1,000 HCCs, clustering patients into subsets with mutational loss or gain of TGF-β pathway activation. Interestingly, patients with the inactivated TGF-β pathway (showing reduced TGFB1, SMAD3, and SMAD4) exhibited a loss of the tumor suppressor genes required for DNA damage repair (ATM, BRCA1, and FANCF), an aberrant expression of pro-oncogenic genes, such as sirtuin and HDAC, and had shorter survival times than those with the activated TGF-β pathway status.…”

Section: Tgf-β In the Pathogenesis Of Hccmentioning

confidence: 99%

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

et al. 2018

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Therapeutic attempts to treat hepatocellular carcinoma (HCC) frequently result in a poor response or treatment failure. The efficacy of approved drugs and survival expectancies is affected by an ample degree of variability that can be explained at least in part by the enormous between-patient cellular and molecular heterogeneity of this neoplasm. Transforming growth factor-β (TGF-β) is hyperactivated in a large fraction of HCCs, where it influences complex interactive networks covering multiple cell types and a plethora of other local soluble ligands, ultimately establishing several malignancy traits. This cytokine boosts the invasiveness of cancerous epithelial cells through promoting the epithelial-to-mesenchymal transition program, but also skews the phenotype of immune cells toward a tumor-supporting status. Here, we discuss recent strategies pursued to offset TGF-β-dependent processes that promote metastatic progression and immune surveillance escape in solid cancers, including HCC. Moreover, we report findings indicating that TGF-β reduces the expression of the proinflammatory factors CCL4 and interleukin-1β (IL-1β in human ex vivo treated HCC tissues. While this is consistent with the anti-inflammatory properties of TGF-β, whether it is an outright tumor promoter or suppressor is still a matter of some debate. Indeed, IL-1β has also been shown to support angiogenesis and cell invasiveness in some cancers. In addition, we describe an inhibitory effect of TGF-β on the secretion of CCL2 and CXCL1 by HCC-derived fibroblasts, which suggests the existence of an indirect stroma-mediated functional link between TGF-β and downstream immunity.

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“…demonstrated that TGFβ upregulates the expression of the CD44 cancer-related CD44V6 isoform through EGR1-mediated AP-1 (activator protein-1) activation in pulmonary fibroblasts. Nevertheless, other studies have clearly highlighted the capacity of TGFβ to restrain the pro-tumorigenic potential of HCC cells, via inducing the expression of tumor suppressors genes, such as LATS1, or DNA damage repair proteins (ATM, BRCA1, and FANCF) 56,57 . A further layer of complexity of the TGFβ role in HCC is suggested by the positive correlation between TGFβ and poor survival, observed only in the patients' subset expressing low PRG4 levels (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Proteoglycan-4 is correlated with longer survival in HCC patients and enhances sorafenib and regorafenib effectiveness via CD44 in vitro

et al. 2020

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Sorafenib and regorafenib administration is among the preferential approaches to treat hepatocellular carcinoma (HCC), but does not provide satisfactory benefits. Intensive crosstalk occurring between cancer cells and other multiple non-cancerous cell subsets present in the surrounding microenvironment is assumed to affect tumor progression. This interplay is mediated by a number of soluble and structural extracellular matrix (ECM) proteins enriching the stromal milieu. Here we assess the HCC tumor expression of the ECM protein proteoglycan 4 (PRG4) and its potential pharmacologic activity either alone, or in combination with sorafenib and regorafenib. PRG4 mRNA levels resulted strongly correlated with increased survival rate of HCC patients (p = 0.000) in a prospective study involving 78 HCC subjects. We next showed that transforming growth factor beta stimulates PRG4 expression and secretion by primary human HCC cancer-associated fibroblasts, non-invasive HCC cell lines, and ex vivo specimens. By functional tests we found that recombinant human PRG4 (rhPRG4) impairs HCC cell migration. More importantly, the treatment of HCC cells expressing CD44 (the main PRG4 receptor) with rhPRG4 dramatically enhances the growth-limiting capacity of sorafenib and regorafenib, whereas not significantly affecting cell proliferation per se. Conversely, rhPRG4 only poorly potentiates drug effectiveness on low CD44-expressing or stably CD44-silenced HCC cells. Overall, these data suggest that the physiologically-produced compound PRG4 may function as a novel tumor-suppressive agent by strengthening sorafenib and regorafenib effects in the treatment of HCC.

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Transforming growth factor-beta1 suppresses hepatocellular carcinoma proliferation via activation of Hippo signaling

Cited by 25 publications

References 29 publications

The Role of TGF-β and Its Receptors in Gastrointestinal Cancers

The Role of TGF-β and Its Receptors in Gastrointestinal Cancers

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

Proteoglycan-4 is correlated with longer survival in HCC patients and enhances sorafenib and regorafenib effectiveness via CD44 in vitro

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