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Expression and inactivation of glycogen synthase kinase 3 alpha/ beta and their association with the expression of cyclin D1 and p53 in oral squamous cell carcinoma progression.

Mishra R, Nagini S, Rana A - Mol. Cancer (2015)

Bottom Line: The increased expression of pS(21)GSK3α and pS(9)GSK3β not only correlated positively with cyclin D1 and p53 expression in tongue cancer progression but a gradual shift of their expression from the cytoplasmic to the nuclear compartment and overall disease severity was also observed.The interaction of GSK3β-cyclin D1 and the positive correlation of pS(9)GSK3β and the transcription of cyclin D1 were observed.These results demonstrate that the inactivation of GSK3β is an important event in OSCC and can be used as a marker for assessing disease severity and may be exploited for therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, 835205, Jharkhand, INDIA. mishrark1@yahoo.co.in.

ABSTRACT

Background: The study aims to evaluate the expression and activity of glycogen synthase kinase 3 isoforms α/β (GSK3α/β) and to assess their oncogenic potential through a correlation with the expression of cyclin D1 and p53 in oral cancer.

Methods: The expression of total and phosphorylated GSK3α/β as well as cyclin D1 and p53 together with their interaction were assessed in human oral cancer tissue samples, apparently normal adjacent tissues, benign tumor samples, premalignant lesions and healthy normal tissues (total 179) using various methods, such as immunohistochemistry, Western blot assays, immunoprecipitation and RT-PCR analysis.

Results: The expression of GSK3β was significantly higher relative to GSK3α indicating the greater role of the β isoform in oral cancer. Among various types of oral cancers, OSCC (of the lip and tongue) showed elevated expression of GSK3α/β, and the expression was correlated with disease progression. The increased expression of pS(21)GSK3α and pS(9)GSK3β not only correlated positively with cyclin D1 and p53 expression in tongue cancer progression but a gradual shift of their expression from the cytoplasmic to the nuclear compartment and overall disease severity was also observed. The interaction of GSK3β-cyclin D1 and the positive correlation of pS(9)GSK3β and the transcription of cyclin D1 were observed.

Conclusions: These results demonstrate that the inactivation of GSK3β is an important event in OSCC and can be used as a marker for assessing disease severity and may be exploited for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus

The interaction of GSK3βwith cyclin D1 in different stages oral cancer progression. (A) The interaction of GSK3β with cyclin D1 in various oral tumor extracts (T1-T2 TE lane 3–5 & 11–13 and T3-T4 TE in lane 6–8 and 14–16). The input IgG and IgG adsorbed in TEs served as controls. (B) The expression levels of GSK3β, pSer9GSK3β, cyclin D1 and β-actin in the TEs were checked in the TEs used for interaction studies. (C) No significant correlation was observed in the interaction of GSK3β-cyclin D1 with the expression of various proteins as indicated.
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Fig6: The interaction of GSK3βwith cyclin D1 in different stages oral cancer progression. (A) The interaction of GSK3β with cyclin D1 in various oral tumor extracts (T1-T2 TE lane 3–5 & 11–13 and T3-T4 TE in lane 6–8 and 14–16). The input IgG and IgG adsorbed in TEs served as controls. (B) The expression levels of GSK3β, pSer9GSK3β, cyclin D1 and β-actin in the TEs were checked in the TEs used for interaction studies. (C) No significant correlation was observed in the interaction of GSK3β-cyclin D1 with the expression of various proteins as indicated.

Mentions: The interaction of GSK3β and cyclin D1 was observed in various oral tumor samples (Figure 6A). Alternatively, a GSK3α-cyclin D1 interaction was not observed. A GSK3β-cyclin D1 association was observed in 100% (6/6) of the higher stage (T3/T4) tumors compared to 66.6% (4/6) of the initial stage (T1/T2) oral tumors samples. The expression of pS9GSK3β, total GSK3β and cyclin D1 was detected in the corresponding WCE (Figure 6B) and was correlated with the extent of the GSK3β-cyclin D1 interaction. The results show no statistically significant correlation between the extent of the GSK3β-cyclin D1 interaction and the level of expression of total GSK3β, pS9GSK3β, and cyclin D1. Moreover, no correlation was observed between the extent of the interaction and the active fraction of GSK3β (arbitrary units of the GSK3β reading minus the pS9GSK3β reading) as shown in Figure 6C.Figure 6


Expression and inactivation of glycogen synthase kinase 3 alpha/ beta and their association with the expression of cyclin D1 and p53 in oral squamous cell carcinoma progression.

Mishra R, Nagini S, Rana A - Mol. Cancer (2015)

The interaction of GSK3βwith cyclin D1 in different stages oral cancer progression. (A) The interaction of GSK3β with cyclin D1 in various oral tumor extracts (T1-T2 TE lane 3–5 & 11–13 and T3-T4 TE in lane 6–8 and 14–16). The input IgG and IgG adsorbed in TEs served as controls. (B) The expression levels of GSK3β, pSer9GSK3β, cyclin D1 and β-actin in the TEs were checked in the TEs used for interaction studies. (C) No significant correlation was observed in the interaction of GSK3β-cyclin D1 with the expression of various proteins as indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4334357&req=5

Fig6: The interaction of GSK3βwith cyclin D1 in different stages oral cancer progression. (A) The interaction of GSK3β with cyclin D1 in various oral tumor extracts (T1-T2 TE lane 3–5 & 11–13 and T3-T4 TE in lane 6–8 and 14–16). The input IgG and IgG adsorbed in TEs served as controls. (B) The expression levels of GSK3β, pSer9GSK3β, cyclin D1 and β-actin in the TEs were checked in the TEs used for interaction studies. (C) No significant correlation was observed in the interaction of GSK3β-cyclin D1 with the expression of various proteins as indicated.
Mentions: The interaction of GSK3β and cyclin D1 was observed in various oral tumor samples (Figure 6A). Alternatively, a GSK3α-cyclin D1 interaction was not observed. A GSK3β-cyclin D1 association was observed in 100% (6/6) of the higher stage (T3/T4) tumors compared to 66.6% (4/6) of the initial stage (T1/T2) oral tumors samples. The expression of pS9GSK3β, total GSK3β and cyclin D1 was detected in the corresponding WCE (Figure 6B) and was correlated with the extent of the GSK3β-cyclin D1 interaction. The results show no statistically significant correlation between the extent of the GSK3β-cyclin D1 interaction and the level of expression of total GSK3β, pS9GSK3β, and cyclin D1. Moreover, no correlation was observed between the extent of the interaction and the active fraction of GSK3β (arbitrary units of the GSK3β reading minus the pS9GSK3β reading) as shown in Figure 6C.Figure 6

Bottom Line: The increased expression of pS(21)GSK3α and pS(9)GSK3β not only correlated positively with cyclin D1 and p53 expression in tongue cancer progression but a gradual shift of their expression from the cytoplasmic to the nuclear compartment and overall disease severity was also observed.The interaction of GSK3β-cyclin D1 and the positive correlation of pS(9)GSK3β and the transcription of cyclin D1 were observed.These results demonstrate that the inactivation of GSK3β is an important event in OSCC and can be used as a marker for assessing disease severity and may be exploited for therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, 835205, Jharkhand, INDIA. mishrark1@yahoo.co.in.

ABSTRACT

Background: The study aims to evaluate the expression and activity of glycogen synthase kinase 3 isoforms α/β (GSK3α/β) and to assess their oncogenic potential through a correlation with the expression of cyclin D1 and p53 in oral cancer.

Methods: The expression of total and phosphorylated GSK3α/β as well as cyclin D1 and p53 together with their interaction were assessed in human oral cancer tissue samples, apparently normal adjacent tissues, benign tumor samples, premalignant lesions and healthy normal tissues (total 179) using various methods, such as immunohistochemistry, Western blot assays, immunoprecipitation and RT-PCR analysis.

Results: The expression of GSK3β was significantly higher relative to GSK3α indicating the greater role of the β isoform in oral cancer. Among various types of oral cancers, OSCC (of the lip and tongue) showed elevated expression of GSK3α/β, and the expression was correlated with disease progression. The increased expression of pS(21)GSK3α and pS(9)GSK3β not only correlated positively with cyclin D1 and p53 expression in tongue cancer progression but a gradual shift of their expression from the cytoplasmic to the nuclear compartment and overall disease severity was also observed. The interaction of GSK3β-cyclin D1 and the positive correlation of pS(9)GSK3β and the transcription of cyclin D1 were observed.

Conclusions: These results demonstrate that the inactivation of GSK3β is an important event in OSCC and can be used as a marker for assessing disease severity and may be exploited for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus