Aging‑associated genes TNFRSF12A and CHI3L1 contribute to thyroid cancer: An evidence for the involvement of hypoxia as a driver

Lian, Meng; Cao, Hongbao; Baranova, Ancha; Kural, Kamil Can; Hou, Lingling; He, Shizhi; Shao, Qing; Fang, Jugao

doi:10.3892/ol.2020.11530

Cited by 13 publications

(14 citation statements)

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“…mega-analysis of RNA expression data sets also demonstrated that CHI3L1 was one of the ageing-associated genes in thyroid cancer and had interactions with signalling molecules such as MAPK1 and AKT1 [38]. A novel finding in this study is that we identified CYR61 participation in tumour-promoting activities mediated by CHI3L1.…”

Section: Chi3l1 Predicts Recurrence In Thyroid Cancer 121supporting

confidence: 58%

Overexpression of chitinase‐3‐like protein 1 is associated with structural recurrence in patients with differentiated thyroid cancer

Cheng

Lee

Chang

et al. 2020

The Journal of Pathology

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We previously identified that the expression of chitinase‐3‐like protein 1 (CHI3L1) was upregulated during thyroid cancer progression. Here, we investigated the prognostic significance of CHI3L1 expression in thyroid neoplasms and examined the potential oncogenic roles. CHI3L1 immunochemical staining was performed on tissue microarrays of benign and malignant thyroid tumours. Compared with normal thyroid tissue and benign thyroid lesions that had low or no detectable CHI3L1 expression, CHI3L1 was overexpressed in both differentiated and undifferentiated thyroid cancer. High CHI3L1 expression was associated with extrathyroidal extension, lymph node metastasis, and shorter recurrence‐free survival in differentiated thyroid cancer. The biological roles of CHI3L1 were further investigated by gain‐ and loss‐of‐function assays. CHI3L1 silencing suppressed clonogenicity, migration, invasion, anoikis resistance, and angiogenesis in thyroid cancer cells, although exogenous CHI3L1 treatment promoted these malignant phenotypes. Cysteine‐rich angiogenic inducer 61 (CYR61) was identified as a downstream target of CHI3L1 by RNA‐seq analysis. CYR61 silencing or treatment reversed the alterations induced by CHI3L1 modulation. Our results demonstrate that CHI3L1 is overexpressed in thyroid cancer and is associated with an increased risk of disease recurrence. Additionally, CYR61 may participate in CHI3L1‐mediated tumour progression. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Chi3l1 Predicts Recurrence In Thyroid Cancer 121supporting

confidence: 58%

Overexpression of chitinase‐3‐like protein 1 is associated with structural recurrence in patients with differentiated thyroid cancer

Cheng

Lee

Chang

et al. 2020

The Journal of Pathology

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“…The CHI3L1 knockdown was associated with suppressed angiogenesis and decreased tumor cell invasion 33 . Moreover, a recent meta‐analysis of RNA expression data sets revealed that CHI3L1 was associated with TC and identified interactions with multiple hypoxia‐driven pathways 34 …”

Section: Discussionmentioning

confidence: 99%

Increased gene expression of TIMP1 and CHI3L1 in fine‐needle aspiration biopsy samples from papillary thyroid cancer as compared to benign nodules

Dimitrova

Shinkov

Dodova

et al. 2021

Diagnostic Cytopathology

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Background Thyroid nodules are common ultrasound findings with malignancy rate 7%–15%. Our objective was to assess the relative expression of the tissue inhibitor of metalloproteinase‐1 gene (TIMP1) and chitinase‐3‐like protein 1 gene (CHI3L1) in fine‐needle aspiration biopsy (FNAB) washouts and the serum levels of their protein products (TIMP‐1 and chitinase‐3‐like protein 1 known as YKL‐40) in patients with papillary thyroid cancer (PTC) and patients with benign nodules. Furthermore, the correlation between gene expression and circulating protein product was evaluated. Methods Eighty patients who underwent FNAB in one tertiary center were recruited in the study. Forty with Bethesda V and VI nodules were operated and PTC was confirmed. The other 40 patients were with Bethesda II nodules. TIMP‐1 and YKL‐40 serum levels were measured in all subjects. The TIMP1 and CHI3L1 expression was assessed in FNAB washouts from 20 PTC patients and 20 benign cases using quantitative PCR. Results The relative expression of TIMP1 and CHI3L1 was significantly higher in the PTC group than in the benign group (p < .001 for TIMP1; p = .018 for CHI3L1). The PTC patients had higher serum TIMP‐1 than the patients with benign nodules (p = .036). We did not find significant difference in the YKL‐40 level between the two groups. TIMP1 and CHI3L1 expression did not correlate with the serum levels of their protein products. Conclusion FNAB washouts could be used for identification of diagnostic markers. The increased TIMP1 and CHI3L1 expression implies a role of these genes in the PTC carcinogenesis.

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“…PSEN1 mutations have been shown to be linked with MTC (60). TNFRSF12A was linked to aging and thyroid cancer (61) and also shown to be a PTC prognostic biomarker in yet another study (62). GPX4 is an essential seleno-protein shown to be associated with aging and cancer (63).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Biomarkers for Predicting Papillary Thyroid Carcinoma Patients at High Risk Using Nine Genes of Apoptotic Pathway

Arora

Kaur

Raghava

2020

Preprint

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ObjectivesAberrant expression of apoptotic genes has been associated with papillary thyroid carcinoma (PTC) in the past, however, their prognostic role and utility as biomarkers remains poorly understood.Materials and methodsIn this study, we analysed 505 PTC patients by employing Cox-PH regression techniques, prognostic index models and machine learning methods to elucidate the relationship between overall survival (OS) of PTC patients and 165 apoptosis related genes.ResultsIt was observed that nine genes (ANXA1, TGFBR3, CLU, PSEN1, TNFRSF12A, GPX4, TIMP3, LEF1, BNIP3L) showed significant association with OS of PTC patients. Five out of nine genes were found to be positively correlated with OS of the patients, while the remaining four genes were negatively correlated. These genes were used for developing risk prediction models. Our voting-based model achieved highest performance (HR=41.59, p=3.36×10−4, C=0.84, logrank-p=3.8×10−8). The performance of voting-based model improved significantly when we used the age of patients with prognostic biomarker genes and achieved HR=57.04 with p=10−4 (C=0.88, logrank-p=1.44×10−9). We also developed classification models that can classify high risk patients (survival ≤ 6 years) and low risk patients (survival > 6 years). Our best model achieved AUROC of 0.92. Since these genes can also be used as potential therapeutic targets in PTC, we identified potential drug molecules which could modulate their expression profile.ConclusionThis study briefly revealed the key prognostic biomarker genes in the apoptotic pathway whose altered expression is associated with PTC progression and aggressiveness. In addition to this, risk assessment models proposed here can help in efficient management of PTC patients.

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Aging‑associated genes TNFRSF12A and CHI3L1 contribute to thyroid cancer: An evidence for the involvement of hypoxia as a driver

Cited by 13 publications

References 51 publications

Overexpression of chitinase‐3‐like protein 1 is associated with structural recurrence in patients with differentiated thyroid cancer

Overexpression of chitinase‐3‐like protein 1 is associated with structural recurrence in patients with differentiated thyroid cancer

Increased gene expression of TIMP1 and CHI3L1 in fine‐needle aspiration biopsy samples from papillary thyroid cancer as compared to benign nodules

Prognostic Biomarkers for Predicting Papillary Thyroid Carcinoma Patients at High Risk Using Nine Genes of Apoptotic Pathway

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