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CSE1L interaction with MSH6 promotes osteosarcoma progression and predicts poor patient survival

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ABSTRACT

To discover tumor-associated proteins in osteosarcoma, a quantitative proteomic analysis was performed to identify proteins that were differentially expressed between osteosarcoma and human osteoblastic cells. Through clinical screening and a functional evaluation, chromosome segregation 1-like (CSE1L) protein was found to be related to the growth of osteosarcoma cells. To date, little is known about the function and underlying mechanism of CSE1L in osteosarcoma. In the present study, we show that knockdown of CSE1L inhibits osteosarcoma growth in vitro and in vivo. By co-immunoprecipitation and RNA-seq analysis, CSE1L was found to interact with mutS homolog 6 (MSH6) and function as a positive regulator of MSH6 protein in osteosarcoma cells. A rescue study showed that decreased growth of osteosarcoma cells by CSE1L knockdown was reversed by MSH6 overexpression, indicating that the activity of CSE1L was an MSH6-dependent function. In addition, depletion of MSH6 hindered cellular proliferation in vitro and in vivo. Notably, CSE1L expression was correlated with MSH6 expression in tumor samples and was associated with poor prognosis in patients with osteosarcoma. Taken together, our results demonstrate that the CSE1L-MSH6 axis has an important role in osteosarcoma progression.

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Clinical significance of CSE1L in patients with osteosarcoma.(A,B) Representative immunohistochemical (IHC) images of CSE1L and MSH6 expression in osteosarcoma tissues. IHC signal intensity scale: negative, low, middle, strong. Original magnification: 50×, 200×. (C–F) The effects of CSE1L expression level and Enneking stage on tumor-free survival and overall survival of patients with osteosarcoma.
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f6: Clinical significance of CSE1L in patients with osteosarcoma.(A,B) Representative immunohistochemical (IHC) images of CSE1L and MSH6 expression in osteosarcoma tissues. IHC signal intensity scale: negative, low, middle, strong. Original magnification: 50×, 200×. (C–F) The effects of CSE1L expression level and Enneking stage on tumor-free survival and overall survival of patients with osteosarcoma.

Mentions: To further determine the clinicopathological significance of CSE1L in osteosarcoma, we performed IHC analysis of CSE1L in a tissue microarray that includes an independent set of 157 cases of osteosarcoma. Representative IHC images of CSE1L expression are shown in Fig. 6A. Correlations between CSE1L expression level and clinicopathological characteristics of patients with osteosarcoma are summarized in Table 1. The expression level of CSE1L was higher in patients at a clinically advanced Enneking stage than at an early stage (P = 0.001). Further analysis found that CSE1L level was positively correlated with recurrence (P < 0.001), indicating that CSE1L has an important role in osteosarcoma recurrence. Univariate analysis showed that tumor-free survival (TFS) was related to CSE1L (P < 0.001) and Enneking stage (P < 0.001). Overall survival (OS) was also related to CSE1L (P = 0.005) and Enneking stage (P = 0.006) (Table 2). Variables that were identified as significantly different in univariate analysis were used for multivariate analysis. The Cox proportional hazards model showed that CSE1L (χ2 = 7.797, HR = 1.358, P = 0.005) and Enneking stage (χ2 = 6.031, HR = 1.898, P = 0.014) were independent prognostic variables for TFS (Table 3). In addition, the Cox proportional hazards model showed that CSE1L (χ2 = 4.236, HR = 1.283, P = 0.040) and Enneking stage (χ2 = 4.030, HR = 1.779, P = 0.045) were independent prognostic variables for OS (Table 3). The OS and TFS curves for this cohort are presented in Fig. 6C,D–F. There was no evidence that any of the other factors, including gender, age, tumor location, tumor necrosis rate, and cortical destruction, significantly influenced prognosis. We also performed Kaplan-Meier survival analyses using microarray data (http://www. kmplot.com) from breast, lung, gastric and ovarian cancer patients. We found that CSE1L expression also correlated negatively with patient survival in other cancers, including breast cancer, gastric cancer and ovarian cancer (Supplementary Figure S6). Finally, we examined MSH6 expression in osteosarcoma tissues; representative images of MSH6 expression are shown in Fig. 6B. We found that there was a significant correlation between expression of both CSE1L and MSH6 in osteosarcoma tissues (R = 0.697, P < 0.001). Based on these findings, CSE1L is correlated with MSH6 in tumor samples and is associated with poor prognosis in patients with osteosarcoma.


CSE1L interaction with MSH6 promotes osteosarcoma progression and predicts poor patient survival
Clinical significance of CSE1L in patients with osteosarcoma.(A,B) Representative immunohistochemical (IHC) images of CSE1L and MSH6 expression in osteosarcoma tissues. IHC signal intensity scale: negative, low, middle, strong. Original magnification: 50×, 200×. (C–F) The effects of CSE1L expression level and Enneking stage on tumor-free survival and overall survival of patients with osteosarcoma.
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Related In: Results  -  Collection

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f6: Clinical significance of CSE1L in patients with osteosarcoma.(A,B) Representative immunohistochemical (IHC) images of CSE1L and MSH6 expression in osteosarcoma tissues. IHC signal intensity scale: negative, low, middle, strong. Original magnification: 50×, 200×. (C–F) The effects of CSE1L expression level and Enneking stage on tumor-free survival and overall survival of patients with osteosarcoma.
Mentions: To further determine the clinicopathological significance of CSE1L in osteosarcoma, we performed IHC analysis of CSE1L in a tissue microarray that includes an independent set of 157 cases of osteosarcoma. Representative IHC images of CSE1L expression are shown in Fig. 6A. Correlations between CSE1L expression level and clinicopathological characteristics of patients with osteosarcoma are summarized in Table 1. The expression level of CSE1L was higher in patients at a clinically advanced Enneking stage than at an early stage (P = 0.001). Further analysis found that CSE1L level was positively correlated with recurrence (P < 0.001), indicating that CSE1L has an important role in osteosarcoma recurrence. Univariate analysis showed that tumor-free survival (TFS) was related to CSE1L (P < 0.001) and Enneking stage (P < 0.001). Overall survival (OS) was also related to CSE1L (P = 0.005) and Enneking stage (P = 0.006) (Table 2). Variables that were identified as significantly different in univariate analysis were used for multivariate analysis. The Cox proportional hazards model showed that CSE1L (χ2 = 7.797, HR = 1.358, P = 0.005) and Enneking stage (χ2 = 6.031, HR = 1.898, P = 0.014) were independent prognostic variables for TFS (Table 3). In addition, the Cox proportional hazards model showed that CSE1L (χ2 = 4.236, HR = 1.283, P = 0.040) and Enneking stage (χ2 = 4.030, HR = 1.779, P = 0.045) were independent prognostic variables for OS (Table 3). The OS and TFS curves for this cohort are presented in Fig. 6C,D–F. There was no evidence that any of the other factors, including gender, age, tumor location, tumor necrosis rate, and cortical destruction, significantly influenced prognosis. We also performed Kaplan-Meier survival analyses using microarray data (http://www. kmplot.com) from breast, lung, gastric and ovarian cancer patients. We found that CSE1L expression also correlated negatively with patient survival in other cancers, including breast cancer, gastric cancer and ovarian cancer (Supplementary Figure S6). Finally, we examined MSH6 expression in osteosarcoma tissues; representative images of MSH6 expression are shown in Fig. 6B. We found that there was a significant correlation between expression of both CSE1L and MSH6 in osteosarcoma tissues (R = 0.697, P < 0.001). Based on these findings, CSE1L is correlated with MSH6 in tumor samples and is associated with poor prognosis in patients with osteosarcoma.

View Article: PubMed Central - PubMed

ABSTRACT

To discover tumor-associated proteins in osteosarcoma, a quantitative proteomic analysis was performed to identify proteins that were differentially expressed between osteosarcoma and human osteoblastic cells. Through clinical screening and a functional evaluation, chromosome segregation 1-like (CSE1L) protein was found to be related to the growth of osteosarcoma cells. To date, little is known about the function and underlying mechanism of CSE1L in osteosarcoma. In the present study, we show that knockdown of CSE1L inhibits osteosarcoma growth in vitro and in vivo. By co-immunoprecipitation and RNA-seq analysis, CSE1L was found to interact with mutS homolog 6 (MSH6) and function as a positive regulator of MSH6 protein in osteosarcoma cells. A rescue study showed that decreased growth of osteosarcoma cells by CSE1L knockdown was reversed by MSH6 overexpression, indicating that the activity of CSE1L was an MSH6-dependent function. In addition, depletion of MSH6 hindered cellular proliferation in vitro and in vivo. Notably, CSE1L expression was correlated with MSH6 expression in tumor samples and was associated with poor prognosis in patients with osteosarcoma. Taken together, our results demonstrate that the CSE1L-MSH6 axis has an important role in osteosarcoma progression.

No MeSH data available.


Related in: MedlinePlus