Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area. 

TGF-β signaling in health, disease, and therapeutics

Background

Under hypoxia, tumour cells undergo genetic and adaptive changes that allow their survival. Previously, we reported that high expression of hypoxia-inducible factor (HIF)-1 was a significant predictive factor for recurrence in hepatocellular carcinoma (HCC). Hypoxia also stimulates expression of procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) genes via the HIF-1 pathway.



Aims

The aim was to evaluate the relationship between hypoxia stress and expression of PLOD genes in HCC in vitro and to identify a new prognostic marker in HCC patients.



Methods

The PLOD2 expression was assessed under hypoxia in hepatoma cell lines and characterized in 139 HCC samples following hepatic resection using microarray experiments, quantitative RT-PCR and immunohistochemistry. Prognostic factors in HCC patients were assessed using univariate and multivariate analyses.



Results

The PLOD2 expression was induced under the hypoxia in vitro. Disease-free survival in the high PLOD2 expression group of HCC patients was significantly shorter when compared with the low-expression group (P = 0.002). In a subset of HCCs, we found that the PLOD2 expression of microarray was correlated with data of quantitative RT-PCR and immunohistochemistry. Of clinicopathological factors, PLOD2 expression was significantly correlated with tumour size (P = 0.022) and macroscopic intrahepatic metastasis (P = 0.049). In univariate analysis, six prognostic factors (tumour multiplicity, macroscopic intrahepatic metastasis, histological grade, microscopic portal invasion, microscopic intrahepatic metastasis and PLOD2 expression) were significant for disease-free survival. PLOD2 expression was identified as a significant, independent factor of poor prognosis (P = 0.013).



Conclusions

PLOD2 is a potential novel prognostic factor for HCC patients following surgery.

PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection.

In the fibrotic kidney, tubular cells undergo epithelial-to-mesenchymal transition (EMT), a phenotypic conversion that is characterized by sequential loss of epithelial markers and gain of mesenchymal features. For understanding of the molecular mechanism that governs this process, a high-throughput gene expression microarray analysis was used to identify the critical genes in the initial phase of the TGF-beta1-mediated EMT. Inhibitor of differentiation-1 (Id1), a dominant negative antagonist of the basic helix-loop-helix transcription factors, was found to be induced rapidly in human proximal tubular epithelial cells after TGF-beta1 treatment. This induction of Id1 depended on intracellular Smad signaling. Ectopic expression of Id1 suppressed epithelial E-cadherin and zonula occludens-1 expression. Id1 physically formed complex with basic helix-loop-helix transcription factor HEB (Hela E-box binding factor), sequestered its ability to bind to E-box, and repressed the trans-activation of E-cadherin promoter. However, overexpression of Id1 failed to induce alpha-smooth muscle actin, matrix metalloproteinase-2, fibronectin, and integrin-linked kinase (ILK), indicating its inability to confer a complete EMT. Overexpression of ILK or inhibition of ILK activity had no effect on Id1 induction by TGF-beta1, suggesting that Id1 and ILK have independent roles in epithelial dedifferentiation and EMT. In vivo, Id1 was induced exclusively in the degenerated, dilated renal tubular epithelium after unilateral ureteral obstruction. These studies identify Id1 transcriptional inhibitor as a crucial player in mediating cell dedifferentiation of renal tubular epithelium and suggest that EMT is a multistep process in which loss of epithelial adhesion does not necessarily lead to an autonomous mesenchymal transition.

Tubular Epithelial Cell Dedifferentiation Is Driven by the Helix-Loop-Helix Transcriptional Inhibitor Id1

Gelatin-based hydrogels are increasingly used to promote cell fate processes in 3D. Here, we report the use of orthogonal thiol–norbornene photochemistry to prepare modularly cross-linked gelatin-based hydrogels for studying the influence of independent matrix properties on hepatocellular carcinoma cell fate in vitro. In addition to demonstrating the ability to independently tune the mechanical and biological properties of modular gelatin–norbornene (GelNB) hydrogels, we also determined that network cross-linking density plays a key role in the mechanisms of proteolytic gel degradation. During in vitro degradation studies, GelNB hydrogels with lower cross-linking density degraded faster and followed a surface erosion mechanism, whereas dense GelNB hydrogels degraded in a bulk degradation mechanism. Hepatocellular carcinoma cells, Huh7, were encapsulated and grown in GelNB hydrogels with modularly tuned stiffness, bioactive motifs, and heparin content. We systematically evaluated the effect of matrix prope...

Modular Cross-Linking of Gelatin-Based Thiol-Norbornene Hydrogels for in Vitro 3D Culture of Hepatocellular Carcinoma Cells.

Clinical Impact of Plasma TGF-β1 and Circulating TGF-β1 mRNA in Diagnosis of Hepatocellular Carcinoma

Transforming growth factor beta 1 (TGF-beta1) is a proposed regulator of Ids (inhibitors of DNA binding/differentiation) gene expression in epithelial cells. We previously reported that Id proteins are variously expressed in human hepatocellular carcinomas (HCC). However, the mechanism of regulation of Ids in HCC remains obscure. Here, we examined the relationship between Id1 and TGF-beta1 in four HCC cell lines, and studied the changes in cell proliferation, cell cycle and differentiation. The four HCC cell lines expressed Id1, TGF-beta1 and their receptors at various levels. TGF-beta1 strongly inhibited the growth of HuH7 cells, while the growth inhibition was moderate in PLC/PRF/5, and was not observed in HLE and HLF cell lines. TGF-beta1-induced growth inhibition in HuH7 cells was associated with cell accumulation in the G1 phase and partial induction of differentiation (with reduction of AFP and AFP-L3). Induction by TGF-beta1 dose-dependently suppressed Id1 expression in HuH7 cells; 1 ng/ml TGF-beta1 inhibited Id1 by 84.0 and 78.6% that of the untreated control at transcriptional and protein levels, respectively. HLE and HLF cells, which did not exhibit a TGF-beta1 growth inhibitory effect, lacked TGF-beta receptors and Id1 expression was not altered. In PLC/PRF/5 cells, Id1 augmentation was not observed in response to TGF-beta1, indicating that TGF-beta1-induced growth inhibition was not related to Id1 in this cell line. Our results suggest that, in some HCC cells, the pathway of suppression of Id1 by TGF-beta1 may be important in TGF-beta1-induced growth inhibition and partial differentiation.

/pdf/tgf-beta1-induced-cell-growth-arrest-and-partial-1hb2cc4jqv.pdf

TGF-beta1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells.

A Case of Gallbladder Carcinoma Producing Alpha-Fetoprotein which was Difficult to Make Differential Diagnosis from Hepatocellular Carcinoma

左眼視力低下を初症状として再発を来した直腸癌の脈絡膜転移症例を経験したので，報告する．症例は49歳の男性で，直腸癌の根治手術15か月後に左眼視力低下を初症状として受診．眼底検査で左眼に，漿液性網膜剥離を伴う脈絡膜腫瘍を認め，胸部CTで両肺に空洞形成を伴う小結節影を多数認めた．経気管支肺生検で腺癌を検出したため，直腸癌の左脈絡膜転移，両側多発性肺転移と診断した．全身化学療法を施行した後，漿液性網膜剥離，網膜下の滲出性変化は改善，脈絡膜腫瘍は縮小し扁平化したが，視力の改善は得られなかった．一方，肺転移は次第に増悪，頸椎転移も出現し，再発後11か月で死亡した．結腸直腸癌の脈絡膜転移報告例は自験例を含め9例とまれであり，報告例は多臓器転移症例が多く，肺，肝転移から2次的に脈絡膜転移を起こす可能性が示唆された．

A Case of Choroidal Metastasis from Rectal Cancer manifesting Visual Loss as the Initial Recurrence Symptom

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TGF-beta1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells.

A Case of Gallbladder Carcinoma Producing Alpha-Fetoprotein which was Difficult to Make Differential Diagnosis from Hepatocellular Carcinoma

A Case of Choroidal Metastasis from Rectal Cancer manifesting Visual Loss as the Initial Recurrence Symptom