PTEN-mediated AKT activation contributes to the reduced apoptosis among Indian oral squamous cell carcinoma patients

Abstract

Purpose: The tumor suppressor gene PTEN negatively regulates Akt, a downstream mediator phosphoinositol 3-kinase. Several studies have reported the role of PTEN gene in Akt downregulation and apoptosis induction in different cancers and cell lines. However, the role of loss of PTEN expression in Akt activation and spontaneous apoptosis in oral squamous cell carcinoma clinical specimens is not well established.

Methods: We investigated the expression of PTEN and phospho-Akt in 146 formalin-fixed (archived) paraffin-embedded oral squamous cell carcinoma tissue sections through immunohistochemical analysis. Programmed cell death (apoptosis) was determined by Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling assay.

Results: Sixty-one percent loss of PTEN expression and 68.5% Akt activation was observed in oral squamous cell carcinoma. A significant correlation was found between loss of PTEN expression and Akt activation. Loss of PTEN expression and Akt activation were further correlated with different clinical parameters and found to be significantly correlated with tumor stage. Apoptotic index was estimated and correlated with PTEN expression and Akt activation. The percentage of apoptotic cells varied from 0.2 to 14.1%. Low apoptotic index was observed in 105 (72%) of samples, and it was found to be significantly related with loss of PTEN expression and phospho-Akt

Conclusion: The present study confirms the contribution of loss of PTEN expression in Akt phosphorylation and spontaneous apoptosis suppression in the specimens of oral cancer. Both PTEN and phospho-Akt are likely to be concerned with oral cancer progression and reduced incidence of spontaneous apoptosis.

Fig. 1

Representative photographs of Immunohistochemical staining and TUNEL assay of poorly differentiated OSCC. a, b Immunostaining for PTEN expression; c, d immunostaining for phospho-Akt at Ser 473. e, f TUNEL assay in OSCC. Tumor to the left shows high PTEN expression with downregulated phosph-Akt and high apoptosis incidence in the same tumor section. a Positive PTEN staining; c phospho-Akt negative staining and e Positive DAB staining (high apoptotic index) in the same tumor section. Tumor to the right is well differentiated SCC show phospho-Akt upregulation in the absence of PTEN expression in the same tissue section. b Negative PTEN immunostaining; d well differentiated SCC showing strong positive phospho-Akt Ser 473 staining (both cytoplasmic and nuclear) and f show negative staining (loss of apoptosis) and. Counter stain for a, b, c and d hematoxylin; for e and f methyl green