Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma
ObjectivesRecently long non-coding RNAs (lncRNAs) have emerged as novel gene regulators involved in tumorigenic processes, including oral squamous cell carcinoma (OSCC). Here, we identified a differentiation-related lncRNA, terminal differentiation-induced non-coding RNA (TINCR). However, its biolog...
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2020.624752/full |
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| author | Zehang Zhuang Zehang Zhuang Jing Huang Jing Huang Weiwang Wang Weiwang Wang Weiwang Wang Cheng Wang Cheng Wang Pei Yu Pei Yu Jing Hu Jing Hu Haichao Liu Haichao Liu Hanqi Yin Hanqi Yin Jinsong Hou Jinsong Hou Xiqiang Liu |
| author_facet | Zehang Zhuang Zehang Zhuang Jing Huang Jing Huang Weiwang Wang Weiwang Wang Weiwang Wang Cheng Wang Cheng Wang Pei Yu Pei Yu Jing Hu Jing Hu Haichao Liu Haichao Liu Hanqi Yin Hanqi Yin Jinsong Hou Jinsong Hou Xiqiang Liu |
| author_sort | Zehang Zhuang |
| collection | DOAJ |
| description | ObjectivesRecently long non-coding RNAs (lncRNAs) have emerged as novel gene regulators involved in tumorigenic processes, including oral squamous cell carcinoma (OSCC). Here, we identified a differentiation-related lncRNA, terminal differentiation-induced non-coding RNA (TINCR). However, its biological function and clinicopathological significance in OSCC still remain unclear.MethodsThe lncRNA expression profiles in OSCC tissues and paired adjacent non-tumor tissues (NATs) from 10 patients were detected by lncRNA microarrays. Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) enrichment were performed to identify the most significant module and module functional annotation, respectively. Potential differentiation-related lncRNAs were screened by differential expression analysis. TINCR was further confirmed in OSCC cell lines and tissues of another patient cohort by using qRT-PCR. The correlation between the TINCR expression level and clinicopathological characteristics was analyzed. The effects of TINCR on cell differentiation, migration and invasion were assessed by knockdown or knock-in in vitro and in vivo.ResultsWGCNA and GO enrichment analysis showed that one co-expression network was significantly enriched for epithelial cell differentiation, among which, TINCR was significantly downregulated. qRT-PCR analyses validated down-regulation of TINCR in tumor tissues compared with paired NATs, and its expression was closely correlated with pathological differentiation and lymph node metastasis in patients with OSCC. Patients with lower TINCR expression levels had worse survival. Cell function experiments showed that TINCR played a crucial role in epithelial differentiation. Both TINCR and epithelial differentiation-associated genes, including IVL and KRT4, were significantly upregulated during OSCC cell calcium-induced differentiation but were reduced when cell dedifferentiation occurred in tumor spheres. Overexpression of TINCR dramatically suppressed cell dedifferentiation, migration and invasion in vitro, while knockdown of TINCR had the opposite effects. Upregulation of TINCR significantly elevated the expression of terminal differentiation genes and repressed tumor growth in vivo. Moreover, TINCR significantly suppressed the activation of JAK2/STAT3 signaling in OSCC cells.ConclusionOur study suggests that TINCR functions as a tumor suppressor by inducing cell differentiation through modulating JAK2/STAT3 signaling in OSCC. TINCR may serve as a prognostic biomarker and therapeutic target for OSCC. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-5e62d619471a4719bc03cfe8d3d4abd42022-12-21T22:10:17ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-02-011010.3389/fonc.2020.624752624752Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell CarcinomaZehang Zhuang0Zehang Zhuang1Jing Huang2Jing Huang3Weiwang Wang4Weiwang Wang5Weiwang Wang6Cheng Wang7Cheng Wang8Pei Yu9Pei Yu10Jing Hu11Jing Hu12Haichao Liu13Haichao Liu14Hanqi Yin15Hanqi Yin16Jinsong Hou17Jinsong Hou18Xiqiang Liu19Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, ChinaDepartment of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, ChinaDepartment of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, ChinaDepartment of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, ChinaDepartment of Prothodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, ChinaGuangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, ChinaDepartment of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, ChinaDepartment of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, ChinaState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaSouth China Institute of Biomedine, Guangzhou, ChinaDepartment of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, ChinaDepartment of Oral and Maxillofacial Surgery, NanFang Hospital, Southern Medical University, Guangzhou, ChinaObjectivesRecently long non-coding RNAs (lncRNAs) have emerged as novel gene regulators involved in tumorigenic processes, including oral squamous cell carcinoma (OSCC). Here, we identified a differentiation-related lncRNA, terminal differentiation-induced non-coding RNA (TINCR). However, its biological function and clinicopathological significance in OSCC still remain unclear.MethodsThe lncRNA expression profiles in OSCC tissues and paired adjacent non-tumor tissues (NATs) from 10 patients were detected by lncRNA microarrays. Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) enrichment were performed to identify the most significant module and module functional annotation, respectively. Potential differentiation-related lncRNAs were screened by differential expression analysis. TINCR was further confirmed in OSCC cell lines and tissues of another patient cohort by using qRT-PCR. The correlation between the TINCR expression level and clinicopathological characteristics was analyzed. The effects of TINCR on cell differentiation, migration and invasion were assessed by knockdown or knock-in in vitro and in vivo.ResultsWGCNA and GO enrichment analysis showed that one co-expression network was significantly enriched for epithelial cell differentiation, among which, TINCR was significantly downregulated. qRT-PCR analyses validated down-regulation of TINCR in tumor tissues compared with paired NATs, and its expression was closely correlated with pathological differentiation and lymph node metastasis in patients with OSCC. Patients with lower TINCR expression levels had worse survival. Cell function experiments showed that TINCR played a crucial role in epithelial differentiation. Both TINCR and epithelial differentiation-associated genes, including IVL and KRT4, were significantly upregulated during OSCC cell calcium-induced differentiation but were reduced when cell dedifferentiation occurred in tumor spheres. Overexpression of TINCR dramatically suppressed cell dedifferentiation, migration and invasion in vitro, while knockdown of TINCR had the opposite effects. Upregulation of TINCR significantly elevated the expression of terminal differentiation genes and repressed tumor growth in vivo. Moreover, TINCR significantly suppressed the activation of JAK2/STAT3 signaling in OSCC cells.ConclusionOur study suggests that TINCR functions as a tumor suppressor by inducing cell differentiation through modulating JAK2/STAT3 signaling in OSCC. TINCR may serve as a prognostic biomarker and therapeutic target for OSCC.https://www.frontiersin.org/articles/10.3389/fonc.2020.624752/fulllncRNAs (long non-coding RNAs)TINCR (tissue differentiation-inducing non-protein coding RNA)OSCC (oral squamous cell carcinoma)cell differentiationmetastasisprogression |
| spellingShingle | Zehang Zhuang Zehang Zhuang Jing Huang Jing Huang Weiwang Wang Weiwang Wang Weiwang Wang Cheng Wang Cheng Wang Pei Yu Pei Yu Jing Hu Jing Hu Haichao Liu Haichao Liu Hanqi Yin Hanqi Yin Jinsong Hou Jinsong Hou Xiqiang Liu Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma Frontiers in Oncology lncRNAs (long non-coding RNAs) TINCR (tissue differentiation-inducing non-protein coding RNA) OSCC (oral squamous cell carcinoma) cell differentiation metastasis progression |
| title | Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma |
| title_full | Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma |
| title_fullStr | Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma |
| title_full_unstemmed | Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma |
| title_short | Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma |
| title_sort | down regulation of long non coding rna tincr induces cell dedifferentiation and predicts progression in oral squamous cell carcinoma |
| topic | lncRNAs (long non-coding RNAs) TINCR (tissue differentiation-inducing non-protein coding RNA) OSCC (oral squamous cell carcinoma) cell differentiation metastasis progression |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2020.624752/full |
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