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Thyroid Hormone Promotes β-Catenin Activation and Cell Proliferation in Colorectal Cancer.

ABSTRACT: Thyroid hormone status has long been implicated in cancer development. Here we investigated the role of thyroxine (T₄) in colorectal cancer cell lines HCT 116 (APC wild type) and HT-29 (APC mutant), as well as the primary cultures of cancer cells derived from patients. Cell proliferation was evaluated with standard assay and proliferation marker expression. β-Catenin activation was examined according to nuclear β-catenin accumulation and β-catenin target gene expression. The results showed that T₄ increased colorectal cancer cell proliferation while cell number and viability were elevated by T₄ in both established cell lines and primary cells. Moreover, the transcriptions of proliferative genes PCNA, CCND1, and c-Myc were enhanced by T₄ in the primary cells. T₄ induced nuclear β-catenin accumulation, as well as high cyclin D1 and c-Myc levels compared to the untreated cells. In addition, the β-catenin-directed transactivation of CCND1 and c-Myc promoters was also upregulated by T₄. CTNNB1 transcription was raised by T₄ in HCT 116, but not in HT-29, while the boosted β-catenin levels were observed in both. Lastly, the T₄-mediated gene expression could be averted by the knockdown of β-catenin. These results suggested that T₄ promotes β-catenin activation and cell proliferation in colorectal cancer, indicating that an applicable therapeutic strategy should be considered.

SUBMITTER: Lee YS

PROVIDER: S-EPMC10355916 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Thyroid Hormone Promotes β-Catenin Activation and Cell Proliferation in Colorectal Cancer.

Lee Yee-Shin YS Chin Yu-Tang YT Shih Ya-Jung YJ Nana André Wendindondé AW Chen Yi-Ru YR Wu Han-Chung HC Yang Yu-Chen S H YSH Lin Hung-Yun HY Davis Paul J PJ

Hormones & cancer 20180129 3

Thyroid hormone status has long been implicated in cancer development. Here we investigated the role of thyroxine (T<sub>4</sub>) in colorectal cancer cell lines HCT 116 (APC wild type) and HT-29 (APC mutant), as well as the primary cultures of cancer cells derived from patients. Cell proliferation was evaluated with standard assay and proliferation marker expression. β-Catenin activation was examined according to nuclear β-catenin accumulation and β-catenin target gene expression. The results s ...[more]

PMID: 29380230

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Project description:Aims: Ribosomal protein L17 (RPL17), a 60S subunit component, is up-regulated in colorectal cancer (CRC). However, its oncogenic role in CRC progression remains unexplored. Thus, we aimed to investigate the effect of RPL17 targeting on CRC in vitro and in vivo and whether RPL17 gained an extra-ribosomal function during CRC development. Methods: RPL17-specific siRNAs complexed with cationic lipids were transfected to CRC cells to silence target gene expression and then real-time RT-PCR and western blotting were applied to observe the change of expression or activity of genes or proteins of interest. Cell proliferation assay, clonogenic assay and cell cycle analysis were used to determine the in vitro effects of RPL17siRNAs on CRC cell growth, and a subcutaneous xenograft assay was applied to test the effect of RPL17siRNAs on in vivo tumor growth. RNA sequencing and western blotting were used to investigate the underlying mechanisms. Sphere-forming assay, invasion assay and migration assay were used to evaluate the effects of RPL17siRNAs on CRC stemness. Results: siRNA-mediated inhibition of RPL17 expression suppressed CRC cell growth and long-term colony formation by inducing apoptotic cell death. Similarly, targeting RPL17 effectively suppressed tumor formation in a mouse xenograft model. RNA sequencing of RPL17-silenced CRC cells revealed the same directional regulation of 159 (93 down- and 66 up-regulated) genes. Notably, NIMA-related kinase 2 (NEK2), which functionally cooperates with extracellular-regulated protein kinase (ERK) and plays a pivotal role in mitotic progression and stemness maintenance, was down-regulated. RPL17 silencing reduced NEK2, β-catenin, and p-ERK protein levels. These molecular alterations reflected the reduction in sphere-forming capacity, expression of stem cell marker genes, migration, and invasion. Reversely, RPL17 overexpression increased the ability of long-term colony formation, migration, and invasion. Conclusion: Our findings indicate that RPL17 promotes CRC proliferation and stemness via the ERK and NEK2/β-catenin signaling axis, and targeting RPL17 could be the next molecular strategy for both primary CRC treatment and prevention of secondary tumor formation.

Dataset Information

Thyroid Hormone Promotes β-Catenin Activation and Cell Proliferation in Colorectal Cancer.

Publications

Thyroid Hormone Promotes β-Catenin Activation and Cell Proliferation in Colorectal Cancer.

Similar Datasets

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