Multidimensional Roles of Collagen Triple Helix Repeat Containing 1 (CTHRC1) in Malignant Cancers

Jiang, Neng; Cui, Yongmei; Liu, Junxiu; Zhu, Xiaolin; Wang, Hui; Yang, Zheng; Ke, Zunfu

doi:10.7150/jca.16539

Cited by 35 publications

(15 citation statements)

References 71 publications

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“…Thus, we concluded that miR-155-5p negatively mediated tumor growth and metastasis of HCC in vitro by CTHRC1 modulation. Furthermore, a great deal of literature has demonstrated that the elevated expression of CTHRC1 was ubiquitously associated with cancer proliferation, invasion, migration, adhesiveness and metastasis and ultimately contributed to the initiation, promotion and progression of cancers, including pancreatic cancer, epithelial ovarian cancer, non-small cell lung cancer and colorectal cancer [ 33 ], which further validated our above stated conclusion. Finally, a xenograft model of BALB/c nude mice was established to certify the impacts of miR-155-5p and CTHRC1 on tumor formation in vivo.…”

Section: Discussionsupporting

confidence: 77%

miR-155-5p modulates malignant behaviors of hepatocellular carcinoma by directly targeting CTHRC1 and indirectly regulating GSK-3β-involved Wnt/β-catenin signaling

et al. 2017

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BackgroundHepatocellular carcinoma (HCC) remains one of the most lethal cancers. MicroRNA-155 (miR-155) and collagen triple helix repeat containing 1 (CTHRC1) were found to be involved in hepatocarcinogenesis, but their detailed functions in HCC are unclear. Here, we aimed to investigate the underlying role of miR-155-5p and CTHRC1 in HCC.MethodsmiR-155-5p and CTHRC1 expression levels were detected by qRT-PCR, IHC and WB in HCC patients and cell lines. Dual-luciferase assay, qRT-PCR and WB were used to validate the target interaction between miR-155-5p and CTHRC1. Biological behaviors, including apoptosis, cell cycle progression, and cell proliferation, invasion and migration, were measured by flow cytometry, CCK-8 assay and Transwell tests. A xenograft model was established to examine the effects of miR-155-5p and CTHRC1 on tumor formation. WB was finally utilized to identify the role of GSK-3β-involved Wnt/β-catenin signaling in HCC growth and metastasis.ResultsOur results showed that miR-155-5p and CTHRC1 were down-regulated and up-regulated, respectively, in HCC patients and cell lines. Dual-luciferase assay verified that CTHRC1 was the direct target of miR-155-5p. Moreover, elevated miR-155-5p expression promoted apoptosis but suppressed cell cycle progression and cell proliferation, invasion and migration in vitro and facilitated tumor formation in vivo; elevated CTHRC1 expression abolished these biological effects. Additionally, miR-155-5p overexpression increased metastasis- and anti-apoptosis-related protein expression and decreased pro-apoptosis-related protein expression, while forced CTHRC1 expression conserved the expression of these proteins.ConclusionAltogether, our data suggested that miR-155-5p modulated the malignant behaviors of HCC by targeting CTHRC1 and regulating GSK-3β-involved Wnt/β-catenin signaling; thereby, miR-155-5p and CTHRC1 might be promising therapeutic targets for HCC patients.Electronic supplementary materialThe online version of this article (10.1186/s12935-017-0469-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 77%

miR-155-5p modulates malignant behaviors of hepatocellular carcinoma by directly targeting CTHRC1 and indirectly regulating GSK-3β-involved Wnt/β-catenin signaling

et al. 2017

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“…Next, we assessed whether pirfenidone altered the expression of targets related to TGF-β1-mediated fibrotic processes in HFL-1 cells. As CTHRC1 and FHL2 are located both in the cytoplasm and nucleus [32, 33], we evaluated the effects of pirfenidone on the localization of the TGF-β1-induced fibrosis regulators using immunofluorescence analysis. TGF-β1 strongly enhanced both CTHRC1 and FHL2 staining, whereas pirfenidone suppressed TGF-β1-induced CTHRC1 and FHL2 expression, including the nuclear localization (fluorescein isothiocyanate stain; green immunofluorescence: Fig.…”

Section: Resultsmentioning

confidence: 99%

Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1

et al. 2019

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Background Pirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-β1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-β1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated. Methods The effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-β1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro. Results Compared to control lung fibroblasts, pirfenidone significantly restored TGF-β1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-β1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of α-smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1. Conclusions Overall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis. Electronic supplementary material The online version of this article (10.1186/s12931-019-1093-z) contains supplementary material, which is available to authorized users.

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“…CTHRC1 (collagen triple helix repeat-containing 1), a 30 kDa glycosylated protein, was first identified in the healing process of injured arteries [22]. There has been a growing enthusiasm for targeting CTHRC1 in the progression and metastasis of various cancers, including NSCLC [23,24,25,26]. For example, CTHRC1 expression at both mRNA and protein levels was significantly higher in NSCLC tumor cells than in adjacent noncancerous tissues [27]; increased serum CTHRC1 has been found in NSCLC patients and positively correlated with metastasis [28]; and CTHRC1 promotes NSCLC cell proliferation and motility, and could be a biomarker of poor prognosis for NSCLC patients [27].…”

Section: Introductionmentioning

confidence: 99%

Loss of Myeloid-Specific TGF-β Signaling Decreases CTHRC1 to Downregulate bFGF and the Development of H1993-Induced Osteolytic Bone Lesions

Ganguly¹,

Daft²,

Cao³

et al. 2018

Cancers

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The role of myeloid cell-specific TGF-β signaling in non-small-cell lung cancer (NSCLC)-induced osteolytic bone lesion development is unknown. We used a genetically engineered mouse model, Tgfbr2LysMCre knockout (KO), which has a loss of TGF-β signaling specifically in myeloid lineage cells, and we found that the area of H1993 cell-induced osteolytic bone lesions was decreased in Tgfbr2LysMCre KO mice, relative to the area in control littermates. The bone lesion areas were correlated with tumor cell proliferation, angiogenesis, and osteoclastogenesis in the microenvironment. The smaller bone lesion area was partially rescued by bFGF, which was expressed by osteoblasts. Interestingly, bFGF was able to rescue the osteoclastogenesis, but not the tumor cell proliferation or angiogenesis. We then focused on identifying osteoclast factors that regulate bFGF expression in osteoblasts. We found that the expression and secretion of CTHRC1 was downregulated in osteoclasts from Tgfbr2LysMCre KO mice; CTHRC1 was able to promote bFGF expression in osteoblasts, possibly through the Wnt/β-catenin pathway. Functionally, bFGF stimulated osteoclastogenesis and inhibited osteoblastogenesis, but had no effect on H1993 cell proliferation. On the other hand, CTHRC1 promoted osteoblastogenesis and H1993 cell proliferation. Together, our data show that myeloid-specific TGF-β signaling promoted osteolytic bone lesion development and bFGF expression in osteoblasts; that osteoclast-secreted CTHRC1 stimulated bFGF expression in osteoblasts in a paracrine manner; and that CTHRC1 and bFGF had different cell-specific functions that contributed to bone lesion development.

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Multidimensional Roles of Collagen Triple Helix Repeat Containing 1 (CTHRC1) in Malignant Cancers

Cited by 35 publications

References 71 publications

miR-155-5p modulates malignant behaviors of hepatocellular carcinoma by directly targeting CTHRC1 and indirectly regulating GSK-3β-involved Wnt/β-catenin signaling

miR-155-5p modulates malignant behaviors of hepatocellular carcinoma by directly targeting CTHRC1 and indirectly regulating GSK-3β-involved Wnt/β-catenin signaling

Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1

Loss of Myeloid-Specific TGF-β Signaling Decreases CTHRC1 to Downregulate bFGF and the Development of H1993-Induced Osteolytic Bone Lesions

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