FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells

Luo, Qin; Wang, Chaoqun; Yang, Lijing; Gao, Xiaomei; Sun, Haoting; Zhang, Yu; Zhang, Kaili; Zhu, Ying; Zheng, Yan; Sheng, Yuan‐Yuan; Lu, Lu; Jia, Hongyan; Yu, Wenqiang; Liu, Jie; Dong, Qiongzhu; Qin, Lun–Xiu

doi:10.1016/j.canlet.2017.12.021

Cited by 65 publications

(49 citation statements)

References 47 publications

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“…Duzgun et al revealed that the overexpression of HSPA4 was correlated with worse OS in head and neck squamous cell carcinoma and breast invasive carcinoma [17]. NDRG1 was demonstrated to be a biomarker for metastasis and indicated poor prognosis in HCC [18,19], which is in line with our study. Lu et al [20] also found NDRG1 was up-regulated in HCC patients and could be used as a potential therapeutic target for HCC.…”

Section: Discussionsupporting

confidence: 92%

Identification of a Five-Immune Gene Model as an Independent Prognostic Factor in Hepatocellular Carcinoma

Chen

Guo

2020

Preprint

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Background: Hepatocellular carcinoma (HCC) is a common cancer with a poor prognosis. We purposed to identify a prognostic risk model of HCC according to the differentially expressed (DE) immune genes.Methods: The DE immune genes were identified based on 374 HCC and 50 adjacent normal samples from the Cancer Genome Atlas database. Univariate Cox analysis, Lasso regression, and multivariate Cox analysis were used to determine the immune genes used to construct the model based on the training group. The testing group and the entire group were applied for the validation of the model.Results: A five-immune gene model comprising HSPA4, ISG20L2, NDRG1, EGF, and IL17D was identified. Based on the model, overall survival was significantly different between the high-risk and low-risk groups (P = 7.953e-06). The AUC for the model at 1- and 3-year was 0.849 and 0.74, respectively. The validating groups confirmed the reliability of the model. The risk score was identified as an independent prognostic factor and was closely related to the content of immune cells from HCC samples.Conclusion: We identified a five-immune gene model, which could be treated as an independent prognostic factor of HCC.

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Section: Discussionsupporting

confidence: 92%

Identification of a Five-Immune Gene Model as an Independent Prognostic Factor in Hepatocellular Carcinoma

Chen

Guo

2020

Preprint

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“…They found that forkhead box Q1 (FOXQ1)/NDRG1 axis in HCC cells could activate pSTAT6/C-C motif chemokine ligand 26 (CCL26) signaling, thus recruiting hepatic stellate cells (HSCs), the main cellular source of cancer associated fibroblast, which is a well-known microenvironment contributor for HCC progression. [ 43 ] Overall, the biological functions of NDRG1 in tumors may vary according to tumor type, which is consistent with the results of our meta-analysis. In future, more studies are required to uncover the concrete mechanisms for the anti- or protumor effects of NDRG1 in different tumors, so as to develop NDRG1 as a therapeutic target.…”

Section: Discussionsupporting

confidence: 91%

“…In addition, some evidence hold on that NDRG1 plays critical role in activating the stress-induced, prosurvival autophagic pathway in cancer cells. [ 41 , 42 ] More interestingly, recently Luo et al [ 43 ] demonstrated that NDRG1 can promote HCC progression by regulating tumor microenvironment. They found that forkhead box Q1 (FOXQ1)/NDRG1 axis in HCC cells could activate pSTAT6/C-C motif chemokine ligand 26 (CCL26) signaling, thus recruiting hepatic stellate cells (HSCs), the main cellular source of cancer associated fibroblast, which is a well-known microenvironment contributor for HCC progression.…”

Section: Discussionmentioning

confidence: 99%

The prognostic value of decreased NDRG1 expression in patients with digestive system cancers

Chen¹,

Liu²,

Wang

et al. 2018

Medicine

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Background:Digestive system cancers are recognized as associated with high morbidity and mortality. It is generally accepted that N-myc downstream-regulated gene 1 (NDRG1) is aberrantly overexpressed or downregulated in digestive system cancers, and its prognostic value remains controversial. Accordingly, we herein conducted a meta-analysis to explore whether NDRG1 expression is correlated with overall survival (OS) and clinicopathological characteristics of patients with digestive system cancers.Methods:We systematically searched PubMed, EMBASE, and Web of Science for eligible studies up to June 6, 2017. In all, 19 publications with 21 studies, were included.Results:The pooled results showed that low NDRG1 expression was significantly associated with worse OS in colorectal cancer (pooled HR = 1.67, 95% CI: 1.22–2.28, P < .001) and pancreatic cancer (pooled HR = 1.87, 95% CI: 1–3.5, P < .0001). Moreover, the relationships between low NDRG1 expression and higher OS ratio of patients with liver cancer (pooled HR = 0.44, 95% CI: 0.32–0.62, P = .009) and gallbladder cancer (pooled HR = 0.56, 95% CI: 0.23–1.38, P = .01) were observed. Nevertheless, no significant association was observed between low NDRG1 expression and OS in gastric cancer (pooled HR = 0.81, 95% CI: 0.45–1.43, P = .46) or esophageal cancer (pooled HR = 0.76, 95% CI: 0.26–2.24, P = .62).Conclusion:The prognostic significance of NDRG1 expression varies according to cancer type in patients with DSCs. Considering that several limitations existed in this meta-analysis, more studies are required to further assess the prognostic value of NDRG1 expression in patients with DSCs and relevant mechanisms.

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“…Previous studies have discussed the source of CAFs and several different opinions existed. Among them, there were studies indicating that HSCs were the main cellular source of CAFs in liver which performed upregulated α-SMA expression once activated by tumor cells [32][33][34] .…”

Section: Discussionmentioning

confidence: 99%

Lysyl oxidase promotes liver metastasis of gastric cancer via facilitating the reciprocal interactions between tumor cells and cancer associated fibroblasts

Zhu

et al. 2019

eBioMedicine

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Background: Liver is one of the most preferred destinations of distant metastasis in gastric cancer (GC). As effective treatment is still limited, the prognosis of GC patients bearing liver metastasis is poor. We filter out lysyl oxidase (LOX) to study its function in the tumor microenvironment (TME) and seek for potential therapeutic targets. Methods: Transcription analysis on 6 cases of liver metastasis of GC patients with respective paired primary tumors and adjacent normal livers was performed. The filtration out of LOX was done using 5 datasets. 69 GC liver metastasis tissues were utilized to perform immunohistochemistry (IHC) and analyze prognosis. Computed Tomography (CT) combined 3D organ reconstruction bioluminescence imaging was performed to precisely evaluate the metastatic tumor burden on liver of intrasplenic injection mouse model. Human and mouse cancer associated fibroblasts (CAFs) in liver metastasis were separated to culture to study the interaction of LOX and TGF-β1. Patients-derived xenograft (PDX) model was established using liver metastasis of patients to evaluate the therapeutic value of LOX inhibitor β-aminopropionitrile (BAPN). Results: CAFs-derived LOX at liver metastatic niche of GC promotes niche formation and outgrowth thus predicts poor prognosis. Meanwhile tumor cells in niche secrete TGF-β1 to nourish CAFs and stimulate them to produce more LOX in turn. The mechanism involved in LOX-mediated proliferation facilitation is enhancement of Warburg effect. The inhibitor of LOX, BPAN could hamper the effect brought by LOX in vivo and in vitro. Interpretation: Our study has unveiled a positive feedback loop between CAFs and tumor cells in liver metastasis niche of GC. The core molecule is LOX which facilitates Warburg effect. Targeting LOX with its inhibitor BAPN might serve as a potential therapeutic strategy.

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FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells

Cited by 65 publications

References 47 publications

Identification of a Five-Immune Gene Model as an Independent Prognostic Factor in Hepatocellular Carcinoma

Identification of a Five-Immune Gene Model as an Independent Prognostic Factor in Hepatocellular Carcinoma

The prognostic value of decreased NDRG1 expression in patients with digestive system cancers

Lysyl oxidase promotes liver metastasis of gastric cancer via facilitating the reciprocal interactions between tumor cells and cancer associated fibroblasts

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