The PTEN tumor suppressor gene and its role in lymphoma pathogenesis.

Xiaoxiao Wang,Huiqiang Huang,Ken H Young

doi:10.18632/aging.100855

Abstract

The phosphatase and tensin homolog gene PTEN is one of the most frequently mutated tumor suppressor genes in human cancer. Loss of PTEN function occurs in a variety of human cancers via its mutation, deletion, transcriptional silencing, or protein instability. PTEN deficiency in cancer has been associated with advanced disease, chemotherapy resistance, and poor survival. Impaired PTEN function, which antagonizes phosphoinositide 3-kinase (PI3K) signaling, causes the accumulation of phosphatidylinositol (3,4,5)-triphosphate and thereby the suppression of downstream components of the PI3K pathway, including the protein kinase B and mammalian target of rapamycin kinases. In addition to having lipid phosphorylation activity, PTEN has critical roles in the regulation of genomic instability, DNA repair, stem cell self-renewal, cellular senescence, and cell migration. Although PTEN deficiency in solid tumors has been studied extensively, rare studies have investigated PTEN alteration in lymphoid malignancies. However, genomic or epigenomic aberrations of PTEN and dysregulated signaling are likely critical in lymphoma pathogenesis and progression. This review provides updated summary on the role of PTEN deficiency in human cancers, specifically in lymphoid malignancies; the molecular mechanisms of PTEN regulation; and the distinct functions of nuclear PTEN. Therapeutic strategies for rescuing PTEN deficiency in human cancers are proposed.

Highlights

The importance of PTEN as a tumor suppressor is further supported by the fact that germline mutations of PTEN commonly occur in a group of autosomal dominant syndromes, including Cowden Syndrome, which are characterized by developmental disorders, neurological deficits, and an increased lifetime risk of cancer and are collectively referred to as PTEN hamartoma tumor syndromes (PHTS) [8, 9]
Since the absent of PTEN is concomitant with phosphoinositide 3-kinase (PI3K) signaling activation, inhibitors that targeting this pathway might play a significant role in the treatment of PTEN-deficient tumors
Growing evidence indicates that multiple solid tumor cell lines and several lymphoid malignancy cell lines with PTEN-deficient are hypersensitive to PI3K inhibitors, which are summarized in Tables 3 and Figure 4

Summary

Introduction

The phosphatase and tensin homolog gene, PTEN, is one of the most commonly mutated tumor suppressors in human malignancies [1,2,3,4,5], and complete loss of PTEN protein expression is significantly associated with advanced cancer and poor outcome [6, 7]. PTEN deficiency has been shown to activate, in a manner dependent on its protein phosphatase activity, the SRC proto-oncogene, non-receptor tyrosine kinase (SRC), thereby conferring resistance to human epidermal growth factor receptor 2 inhibition [19]. Positive regulators of PTEN gene expression include early growth response protein 1, peroxisome proliferatoractivated receptor γ (PPARγ) and P53, which have been shown to directly bind to the PTEN promoter region [27,28,29].

Results

Conclusion