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Stanniocalcin 2 (STC2) expression promotes post-radiation survival, migration and invasion of nasopharyngeal carcinoma cells.

ABSTRACT: Background: Stanniocalcin 2 (STC2) expression is upregulated under multiple stress conditions including hypoxia, nutrient starvation and radiation. Overexpression of STC2 correlates with tumor progression and poor prognosis. Purpose: We previously demonstrated that overexpression of STC2 in nasopharyngeal carcinomas (NPC) positively correlates with radiation resistance and tumor metastasis, two major clinical obstacles to the improvement of NPC management. However, it remains elusive whether STC2 expression is a critical contributing factor for post-radiation survival and metastasis of NPC cells. Materials and methods: Using the radiation resistant CNE2 cell line as a model, we examined the importance of STC2 expression for post-radiation survival, migration and invasion. Here, we report the establishment of STC2 knockout lines (CNE2-STC2-KO) using the CRISPR/Cas9-based genome editing technique. Results: Compared with the parental line, STC2-KO cells showed similar proliferation and morphology in normal culture conditions, and loss of STC2 did not compromise the cell tumorigenicity in nude mice model. However, STC2-KO lines demonstrated increased sensitivity to X-radiation under either normoxic or hypoxic conditions. Particularly, upon X-radiation, parental CNE2 cells only slightly whereas STC2-KO cells remarkably decreased the migration and invasion ability. Cell cycle analysis revealed that loss of STC2 accumulated cells in G1 and G2/M phases but decreased S-population. Conclusion: These data indicate that the expression of STC2, which can be stimulated by metabolic or therapeutic stresses, is one important factor to promote survival and metastasis of post-radiation NPC cells. Therefore, targeting STC2 or relative downstream pathways may provide novel strategies to overcome radiation resistance and metastasis of NPC.

SUBMITTER: He H

PROVIDER: S-EPMC6636319 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Stanniocalcin 2 (STC2) expression promotes post-radiation survival, migration and invasion of nasopharyngeal carcinoma cells.

He Huocong H Qie Shuo S Guo Qiaojuan Q Chen Shuyang S Zou Changyan C Lu Tianzhu T Su Ying Y Zong Jingfeng J Xu Hanchuan H He Dan D Xu Yun Y Chen Bijuan B Pan Jianji J Sang Nianli N Lin Shaojun S

Cancer management and research 20190711

<b>Background:</b> Stanniocalcin 2 (STC2) expression is upregulated under multiple stress conditions including hypoxia, nutrient starvation and radiation. Overexpression of STC2 correlates with tumor progression and poor prognosis. <b>Purpose:</b> We previously demonstrated that overexpression of STC2 in nasopharyngeal carcinomas (NPC) positively correlates with radiation resistance and tumor metastasis, two major clinical obstacles to the improvement of NPC management. However, it remains elusi ...[more]

PMID: 31372045

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Project description:The authors' previous study revealed that the serum levels of microRNA (miR)-663b are significantly increased in patients with nasopharyngeal carcinoma (NPC), and are associated with NPC progression and poor prognosis. However, the molecular mechanism of underlying NPC growth and metastasis remains unclear. In the present study, quantitative polymerase chain reaction and western blot analyses were performed to examine changes to mRNA and protein expression, respectively. MTT, wound healing and Transwell assays were used to examine cell proliferation, migration and invasion, respectively. Luciferase reporter gene assays were performed to identify target genes of miR-663b. It was demonstrated that miR-663b was significantly upregulated in NPC tissue compared with non-tumor nasopharyngeal epithelial tissue samples. Furthermore, miR-663b expression gradually increased with advancing stages of NPC, with the highest expression being observed in the latest stage IV. The increased expression of miR-663b was associated with advanced clinical stage and lymph node metastasis. In addition, miR-663b expression was increased in NPC cell lines compared with normal nasopharyngeal epithelial NP69 cells. Knockdown of miR-663b resulted in a significant reduction in the proliferation, migration and invasion of NPC CNE1 cells. Tumor suppressor candidate 2 (TUSC2) was identified as a novel target gene of miR-663b. It was further demonstrated that TUSC2 was significantly downregulated in NPC tissue samples and cell lines. miR-663b negatively regulated the expression of TUSC2 at the post-transcriptional level in CNE1 cells. Additionally, inhibition of TUSC2 expression attenuated the suppressive effects of miR-663b downregulation on the proliferation, migration and invasion of CNE1 cells. To the best of our knowledge, this is the first study to demonstrate that miR-663b, which is upregulated in NPC, promotes the proliferation, migration and invasion of NPC cells, partially through the inhibition of TUSC2 expression. Therefore, it is suggested that miR-663b is a promising therapeutic target for the treatment of patients with NPC.

Project description:BackgroundOverexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a DNA/RNA binding protein, is associated with metastasis in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying hnRNP K-mediated metastasis is unclear. The aim of the present study was to determine the role of matrix metalloproteinase (MMP) in hnRNP K-mediated metastasis in NPC.MethodsWe studied hnRNP K-regulated MMPs by analyzing the expression profiles of MMP family genes in NPC tissues and hnRNP K-knockdown NPC cells using Affymetrix microarray analysis and quantitative RT-PCR. The association of hnRNP K and MMP12 expression in 82 clinically proven NPC cases was determined by immunohistochemical analysis. The hnRNP K-mediated MMP12 regulation was determined by zymography and Western blot, as well as by promoter, DNA pull-down and chromatin immunoprecipitation (ChIP) assays. The functional role of MMP12 in cell migration and invasion was demonstrated by MMP12-knockdown and the treatment of MMP12-specific inhibitor, PF-356231.ResultsMMP12 was overexpressed in NPC tissues, and this high level of expression was significantly correlated with high-level expression of hnRNP K (P?=?0.026). The levels of mRNA, protein and enzyme activity of MMP12 were reduced in hnRNP K-knockdown NPC cells. HnRNP K interacting with the region spanning -42 to -33 bp of the transcription start site triggered transcriptional activation of the MMP12 promoter. Furthermore, inhibiting MMP12 by MMP12 knockdown and MMP12-specific inhibitor, PF-356231, significantly reduced the migration and invasion of NPC cells.ConclusionsOverexpression of MMP12 was significantly correlated with hnRNP K in NPC tissues. HnRNP K can induce MMP12 expression and enzyme activity through activating MMP12 promoter, which promotes cell migration and invasion in NPC cells. In vitro experiments suggest that NPC metastasis with high MMP12 expression may be treated with PF-356231. HnRNP K and MMP12 may be potential therapeutic markers for NPC, but additional validation studies are warranted.

Dataset Information

Stanniocalcin 2 (STC2) expression promotes post-radiation survival, migration and invasion of nasopharyngeal carcinoma cells.

Publications

Stanniocalcin 2 (STC2) expression promotes post-radiation survival, migration and invasion of nasopharyngeal carcinoma cells.

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