Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/β‐catenin signaling and sensitizes cancer cells to FH535 therapy

Autor: Yu-Long Wang, Tian Liao, Ning Qu, Duo Wen, Ben Ma, Zhong Wu Lu, Qinghai Ji, Wen Jun Wei, Rong Liang Shi
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Cancer Research
endocrine system diseases
Apoptosis
Papillary thyroid cancer
CSN6
Mice
0302 clinical medicine
Cell Movement
Tumor Cells
Cultured
Thyroid cancer
beta Catenin
Original Research
Gene knockdown
Mice
Inbred BALB C
Sulfonamides
Chemistry
Wnt signaling pathway
EMT
Middle Aged
Prognosis
Gene Expression Regulation
Neoplastic
Oncology
030220 oncology & carcinogenesis
Lymphatic Metastasis
Disease Progression
Female
proliferation
FH535
Mice
Nude
Wnt1 Protein
03 medical and health sciences
Downregulation and upregulation
medicine
Biomarkers
Tumor
Cell Adhesion
Gene silencing
Animals
Humans
Radiology
Nuclear Medicine and imaging
papillary thyroid cancer
Wnt/β‐catenin signaling pathway
Thyroid Neoplasms
Adaptor Proteins
Signal Transducing
Cell Proliferation
COP9 Signalosome Complex
Cancer
Clinical Cancer Research
medicine.disease
Xenograft Model Antitumor Assays
Carcinoma
Papillary
030104 developmental biology
Drug Resistance
Neoplasm
Cancer cell
Cancer research
Follow-Up Studies
Zdroj: Cancer Medicine
ISSN: 2045-7634
Popis: The incidence of thyroid cancer has increased worldwide at a rate higher than that of any other cancer. CSN6 is overexpressed in many types of cancers, and such expression is linked to oncogenic activity. However, the detailed biological functions of CSN6 in papillary thyroid cancer (PTC) have not been well characterized. We investigated CSN6 expression in PTC specimens and cell lines. We used short‐hairpin RNA‐mediated gene silencing to explore the biological effects of CSN6 depletion in PTC cells. The combined effects of CSN6 silencing and FH535 therapy were assessed in terms of cell viability. The mechanism by which CSN6 regulated β‐catenin expression was also analyzed. CSN6 levels were determined by real‐time polymerase chain reaction (PCR) (mRNA), Western blotting, and immunochemistry (protein). The CCK‐8 and migration assays and orthotopic xenograft transplantation were used to investigate the biological effects of CSN6. We assessed the combined effects of CSN6 silencing and FH535 on cell viability in vitro. We also analyzed the relationship between the CSN6 level and clinical pathological status. CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration both in vitro and in vivo. CSN6 stabilized β‐catenin and facilitated the epidermal‐to‐mesenchymal transition (EMT) in PTC cells. CSN6 positively regulated β‐catenin expression in a β‐Trcp‐dependent manner and triggered expression of several EMT‐related genes regulated by β‐catenin. CSN6 silencing sensitized PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway. Finally, in PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage. CSN6 overexpression in PTC is a strong indicator of enhanced tumor aggressiveness. CSN6 promotes PTC progression by inducing the EMT. CSN6 knockdown sensitizes PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway.
Databáze: OpenAIRE
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