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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 expression of GSK3α/βproteins at various stages of OSCC progression. (A) Representative immunostaining showing the differential expression of GSK3α and GSK3β from consecutive sections of lip SCC tissue progression, including (a, b) normal lip, (c, d) hyperplasia of the lip and (e, f) SCC of the lip. (B) Representative immunostaining showing the differential expression of GSK3α and GSK3β from consecutive sections of OTSCC tissue progression, including (a, b) normal tongue; (c, d) hyperplasia of the tongue and (e, f) SCC of the tongue. (C) Photomicrographs showing distant metastasis of SCC cells at the lymph nodes from various OSCC showing immunoreactivity to GSK3α and GSK3β antibodies to different extents in the consecutive sections (a to h). The metastatic OTSCC showed maximum expression of GSK3β (original magnification 100X).
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Fig3: The expression of GSK3α/βproteins at various stages of OSCC progression. (A) Representative immunostaining showing the differential expression of GSK3α and GSK3β from consecutive sections of lip SCC tissue progression, including (a, b) normal lip, (c, d) hyperplasia of the lip and (e, f) SCC of the lip. (B) Representative immunostaining showing the differential expression of GSK3α and GSK3β from consecutive sections of OTSCC tissue progression, including (a, b) normal tongue; (c, d) hyperplasia of the tongue and (e, f) SCC of the tongue. (C) Photomicrographs showing distant metastasis of SCC cells at the lymph nodes from various OSCC showing immunoreactivity to GSK3α and GSK3β antibodies to different extents in the consecutive sections (a to h). The metastatic OTSCC showed maximum expression of GSK3β (original magnification 100X).

Mentions: Statistics were gathered to determine the expression of GSK3α and GSK3β in OSCC progression. The results showed that in the normal lip, no immunoreactivity was observed for both the GSK3α and the GSK3β antibody (Figure 3A (a, b)). However, in the normal tongue tissue, mild expression of the GSK3α/β protein was observed in the peripheral epithelial layer in most of the cases (Figure 3B (a, b)), except one sample that showed strong immunoreactivity to the GSK3β antibody. In the tissue samples with mild hyperplasia, the expression of GSK3α and GSK3β was observed, and it was limited to the deeper epithelial zone of both the lip and tongue tissues (Figure 3A (c, d) & B (c, d)). Alternatively, the expression of the GSK3α/β protein was observed in the tumors of the lip and tongue (Figure 3A (e, f) & B (e, f)). In the OTSCC progression model, a total of twenty-two samples were analyzed, and GSK3β overexpression was observed in 14.2% (1/7) of normal samples, in 20.0% (1/5) of hyperplasia and 70.0% (7/10) of cancer samples (p = 0.0396). In the lip cancer progression model, a total of fifteen samples were analyzed and GSK3β overexpression was not observed in normal (n = 2) or hyperplasia (n = 3) samples but was observed in 70.0% (7/10) of cancer samples (p = 0.0376). In the distant metastatic SCC samples, the invasive cancer cells at the new location demonstrated an overexpression of GSK3β in 87.5% (7/8) whereas only 12.5% (1/8) of samples showed an overexpression of GSK3α (p = 0.002) (Table 1 and Figure 3C (a to h)). Similarly, nearby lymph node positive cases were found in 60% (3/5) of the GSK3β overexpressing tumors and in only 20% (1/5) of the GSK3α overexpressing tumors.Figure 3


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 expression of GSK3α/βproteins at various stages of OSCC progression. (A) Representative immunostaining showing the differential expression of GSK3α and GSK3β from consecutive sections of lip SCC tissue progression, including (a, b) normal lip, (c, d) hyperplasia of the lip and (e, f) SCC of the lip. (B) Representative immunostaining showing the differential expression of GSK3α and GSK3β from consecutive sections of OTSCC tissue progression, including (a, b) normal tongue; (c, d) hyperplasia of the tongue and (e, f) SCC of the tongue. (C) Photomicrographs showing distant metastasis of SCC cells at the lymph nodes from various OSCC showing immunoreactivity to GSK3α and GSK3β antibodies to different extents in the consecutive sections (a to h). The metastatic OTSCC showed maximum expression of GSK3β (original magnification 100X).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: The expression of GSK3α/βproteins at various stages of OSCC progression. (A) Representative immunostaining showing the differential expression of GSK3α and GSK3β from consecutive sections of lip SCC tissue progression, including (a, b) normal lip, (c, d) hyperplasia of the lip and (e, f) SCC of the lip. (B) Representative immunostaining showing the differential expression of GSK3α and GSK3β from consecutive sections of OTSCC tissue progression, including (a, b) normal tongue; (c, d) hyperplasia of the tongue and (e, f) SCC of the tongue. (C) Photomicrographs showing distant metastasis of SCC cells at the lymph nodes from various OSCC showing immunoreactivity to GSK3α and GSK3β antibodies to different extents in the consecutive sections (a to h). The metastatic OTSCC showed maximum expression of GSK3β (original magnification 100X).
Mentions: Statistics were gathered to determine the expression of GSK3α and GSK3β in OSCC progression. The results showed that in the normal lip, no immunoreactivity was observed for both the GSK3α and the GSK3β antibody (Figure 3A (a, b)). However, in the normal tongue tissue, mild expression of the GSK3α/β protein was observed in the peripheral epithelial layer in most of the cases (Figure 3B (a, b)), except one sample that showed strong immunoreactivity to the GSK3β antibody. In the tissue samples with mild hyperplasia, the expression of GSK3α and GSK3β was observed, and it was limited to the deeper epithelial zone of both the lip and tongue tissues (Figure 3A (c, d) & B (c, d)). Alternatively, the expression of the GSK3α/β protein was observed in the tumors of the lip and tongue (Figure 3A (e, f) & B (e, f)). In the OTSCC progression model, a total of twenty-two samples were analyzed, and GSK3β overexpression was observed in 14.2% (1/7) of normal samples, in 20.0% (1/5) of hyperplasia and 70.0% (7/10) of cancer samples (p = 0.0396). In the lip cancer progression model, a total of fifteen samples were analyzed and GSK3β overexpression was not observed in normal (n = 2) or hyperplasia (n = 3) samples but was observed in 70.0% (7/10) of cancer samples (p = 0.0376). In the distant metastatic SCC samples, the invasive cancer cells at the new location demonstrated an overexpression of GSK3β in 87.5% (7/8) whereas only 12.5% (1/8) of samples showed an overexpression of GSK3α (p = 0.002) (Table 1 and Figure 3C (a to h)). Similarly, nearby lymph node positive cases were found in 60% (3/5) of the GSK3β overexpressing tumors and in only 20% (1/5) of the GSK3α overexpressing tumors.Figure 3

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