Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC)

Srivastava, Jyoti; Robertson, Chadia L.; Gredler, Rachel; Siddiq, Ayesha; Rajasekaran, Devaraja; Akiel, Maaged; Emdad, Luni; Mas, Valeria R.; Mukhopadhyay, Nitai D.; Fisher, Paul B.; Sarkar, Devanand

doi:10.1074/jbc.m115.649707

Cited by 22 publications

(17 citation statements)

References 33 publications

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“…However, after grouping patients into early-intermediate (BCLC A-B) and advanced-terminal stage (BCLC C-D), the negative impact of elevated fT 4 on survival remained significant in both subgroups. Additionally, non-thyroidal illness syndrome (NTIS), characterized by low serum T 3 with normal T 4 levels, is associated with HCC and other malignancies [ 46 , 47 ]. The fact that T 3 and fT 3 levels were missing in most of our patients represents another potential bias we could not address in our analysis.…”

Section: Discussionmentioning

confidence: 99%

The impact of thyroid hormones on patients with hepatocellular carcinoma

et al. 2017

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Background & aimsHypothyroidism has recently been proposed as predisposing factor for HCC development. However, the role of thyroid hormones (TH) in established HCC is largely unclear. We investigated the impact of TH on clinical characteristics and prognosis of HCC patients.MethodsOf 838 patients diagnosed with nonsurgical HCC at the Division of Gastroenterology and Hepatology/Medical University of Vienna between 1992 and 2012, 667 patients fulfilled the inclusion criteria. The associations of thyroid function tests with patient, liver, and tumor characteristics as well as their impact on overall survival (OS) were investigated.ResultsThyroid hormone substitution was more often observed in patients with low thyroid-stimulating hormone (TSH) concentration and in patients with elevated free tetraiodthyronine (fT4). Patients with high TSH (>3.77uU/ml) concentrations had larger tumors, while the opposite was true for patients with low TSH (<0.44uU/ml) concentrations. Subjects with elevated fT4 (>1.66ng/dl) were more likely to have elevated CRP. While TSH was only associated with OS in univariate analysis (≤1.7 vs. >1.7uU/ml, median OS (95%CI), 12.3 (8.9–15.7 months) vs. 7.3 months (5.4–9.2 months); p = 0.003), fT4 (≤1.66 vs. >1.66ng/dl, median OS (95%CI), 10.6 (7.5–13.6 months) vs. 3.3 months (2.2–4.3 months); p = 0.007) remained an independent prognostic factor for OS (HR (95%CI) for fT4>1.66ng/dl, 2.1 (1.3–3.3); p = 0.002) in multivariate analysis.ConclusionsTSH and fT4 were associated with prognostic factors of HCC (i.e., tumor size, CRP level). Elevated fT4 concentrations were independently associated with poor prognosis in HCC. Further studies are needed to characterize the role of TH in HCC in detail.

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Section: Discussionmentioning

confidence: 99%

The impact of thyroid hormones on patients with hepatocellular carcinoma

et al. 2017

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“…This study concurs that the expression levels of both mRNA and protein MTDH were significantly upregulated in the 20 HCC tissues compared to the matched normal adjacent tissues. MTDH contributes to HCC initiation and progression by a variety of mechanisms, such as interference with thyroid hormone (T3) function, downregulation of type I 5'-deiodinase (DIO1) level, a local hypothyroid state creation in the liver, activation of nuclear factor κB (NF-κB) and other protumorigenic signaling pathways (32). Knockdown of MTDH inhibits proliferation, invasion and notably abolishes cancer onset, growth and metastasis (33,34).…”

Section: Discussionmentioning

confidence: 99%

miR-217 suppresses proliferation, migration, and invasion promoting apoptosis via targeting MTDH in hepatocellular carcinoma

Zhang

et al. 2017

Oncology Reports

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Hepatocellular carcinoma (HCC) has frequent incidence and the third highest mortality rate among cancers in the world. This study aimed to clarify the roles of miR-217 and metadherin (MTDH) in HCC. First, we identified that miR-217 expression was downregulated and MTDH expression was upregulated in the HCC tissues. Functional studies revealed that miR-217 negatively regulated MTDH expression via binding to the 3'-untranslated region of MTDH mRNA in the HCC cells. In our further studies, the miR-217 overexpression resulted in downregulation of MTDH expression in HCC cells. The miR-217 overexpression in HCC cells suppressed proliferation, migration, and invasion inducing apoptosis. Taken together, our study provides the initial evidence that the increase of MTDH expression is associated with the decrease of miR-217 expression in HCC. This study also suggests that miR-217 inhibits malignant progression of HCC in vitro and may be used for miRNA-based therapy, possibly via directly targeting MTDH.

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“…The AEG-1 gene is an oncogene, which is located at chromosome 8q22 [ 5 ], and it is observed that elevated expression of AEG-1 promoted tumor proliferation, progression or metastasis in multiple carcinomas such as EC [ 6 ], HCC [ 7 ], neuroblastoma [ 8 ], breast cancer [ 9 ], prostate cancer [ 10 ] and malignant glioma [ 11 ]. In addition, AEG-1 could activate multiple molecular mechanisms to exert its functions, including nuclear factor κ-B (NF-κB) [ 12 ], phosphatidylinositol 3-kinase (PI3K)/Akt and c-Myc [ 13 , 14 ], Wnt/b-catenin [ 15 ], extracellular signal-regulated kinase (ERK) [ 7 ], activator protein 1 (AP-1) [ 10 ] and non-thyroidal illness syndrome (NTIS) [ 16 ]. Also, it was reported that AEG-1 could increase the expression of angiopoietin-1, matrix metalloprotease-2 (MMP2), hypoxia-inducible factor 1-α (HIF-α) and Tie2, which are essential in angiogenesis [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Astrocyte Elevated Gene-1 as a Novel Clinicopathological and Prognostic Biomarker for Gastrointestinal Cancers: A Meta-Analysis with 2999 Patients

et al. 2015

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BackgroundThere have been numerous articles as to whether the staining index (SI) of astrocyte elevated gene-1 (AEG-1) adversely affects clinical progression and prognosis of gastrointestinal cancers. Nevertheless, controversy still exists in terms of correlations between AEG-1 SI and clinicopathological parameters including survival data. Consequently, we conducted a comprehensive meta-analysis to confirm the role of AEG-1 in clinical outcomes of gastrointestinal carcinoma patients.MethodsWe performed a comprehensive search in PubMed, ISI Web of Science, Cochrane Central Register of Controlled Trials, EMBASE, Science Direct, Wiley Online Library, China National Knowledge Infrastructure (CNKI), WanFang and Chinese VIP databases. STATA 12.0 (STATA Corp., College, TX) was used to analyze the data extracted from suitable studies and Newcastle-Ottawa Scale was applied to assess the quality of included articles.ResultsThe current meta-analysis included 2999 patients and our results suggested that strong associations emerged between AEG-1 SI and histological differentiation (OR = 2.129, 95%CI: 1.377–3.290, P = 0.001), tumor (T) classification (OR = 2.272, 95%CI: 1.147–4.502, P = 0.019), lymph node (N) classification (OR = 2.696, 95%CI: 2.178–3.337, P<0.001) and metastasis (M) classification (OR = 3.731, 95%CI: 2.167–6.426, P<0.001). Furthermore, high AEG-1 SI was significantly associated with poor overall survival (OS) (HR = 2.369, 95%CI: 2.005–2.800, P<0.001) and deteriorated disease-free survival (DFS) (HR = 1.538, 95%CI: 1.171–2.020, P = 0.002). For disease-specific survival (DSS) and relapse-free survival (RFS), no statistically significant results were observed (HR = 1.573, 95%CI: 0.761–3.250, P = 0.222; HR = 1.432, 95%CI: 0.108–19.085, P = 0.786). Subgroup analysis demonstrated that high AEG-1 SI was significantly related to poor prognosis in esophageal squamous cell carcinoma (ESCC) (HR = 1.715, 95%CI: 1.211–2.410, P = 0.002), gastric carcinoma (GC) (HR = 2.255, 95%CI: 1.547–3.288, P<0.001), colorectal carcinoma (CRC) (HR = 2.922, 95%CI: 1.921–4.444, P<0.001), gallbladder carcinoma (GBC) (HR = 3.047, 95%CI: 1.685–5.509, P<0.001), hepatocellular carcinoma (HCC) (HR = 2.245, 95%CI: 1.620–3.113, P<0.001), pancreatic adenocarcinoma (PAC) (HR = 2.408, 95%CI: 1.625–3.568, P<0.001).ConclusionsThe current meta-analysis indicated that high AEG-1 SI might be associated with tumor progression and poor survival status in patients with gastrointestinal cancer. AEG-1 might play a vital role in promoting tumor aggression and could serve as a potential target for molecular treatments. Further clinical trials are needed to validate whether AEG-1 SI provides valuable insights into improving treatment decisions.

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Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC)

Cited by 22 publications

References 33 publications

The impact of thyroid hormones on patients with hepatocellular carcinoma

The impact of thyroid hormones on patients with hepatocellular carcinoma

miR-217 suppresses proliferation, migration, and invasion promoting apoptosis via targeting MTDH in hepatocellular carcinoma

Astrocyte Elevated Gene-1 as a Novel Clinicopathological and Prognostic Biomarker for Gastrointestinal Cancers: A Meta-Analysis with 2999 Patients

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