The role of phosphatase and tensin homolog on chromosome 10 (PTEN) as a tumor suppressor has been for a long time attributed to its lipid phosphatase activity against PI(3,4,5)P3, the phospholipid product of the class I PI3Ks. Besides its traditional role as a lipid phosphatase at the plasma membrane, a wealth of data has shown that PTEN can function independently of its phosphatase activity and that PTEN also exists and plays a role in the nucleus, in cytoplasmic organelles, and extracellularly. Accumulating evidence has shed light on diverse physiological functions of PTEN, which are accompanied by a complex regulation of its expression and activity. PTEN levels and function are regulated transcriptionally, post-transcriptionally, and post-translationally. PTEN is also sensitive to regulation by its interacting proteins and its localization. Herein, we summarize the current knowledge on mechanisms that regulate the expression and enzymatic activity of PTEN and its role in human diseases.

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Focus on PTEN Regulation

Gastric cancer is highly invasive, aggressively malignant, and amongst the most prevalent of all forms of cancer. Despite improved management strategies, early stage diagnosis of gastric cancer and accurate prognostic assessment is still lacking. Several recent reports have indicated that the pathogenesis of gastric cancer involves complex molecular mechanisms and multiple genetic and epigenetic alterations in oncogenes and tumor suppressor genes. Functional inactivation of the tumor suppressor protein PTEN (Phosphatase and Tensin Homolog) has been detected in multiple cases of gastric cancer, and already shown to be closely linked to the development, progression and prognosis of the disease. Inactivation of PTEN can be attributed to gene mutation, loss of heterozygosity, promoter hypermethylation, microRNA- mediated regulation of gene expression, and post-translational phosphorylation. PTEN is also involved in mechanisms regulating tumor resistance to chemotherapy. This review provides a comprehensive analysis of PTEN and its roles in gastric cancer, and emphasizes its potential benefits in early diagnosis and gene therapy-based tr eatment strategies.

http://koreascience.or.kr:80/article/JAKO201417638007811.pdf

Roles of PTEN (Phosphatase and Tensin Homolog) in gastric cancer development and progression.

Occurrence of breast cancer is related to genetic as well as cultural, environmental and life-style factors. Variations in diversity of these factors among different ethnic groups and geographical areas emphasize the immense need for studies in all racial-ethnic populations. The incidence of breast cancer in Pakistan is highest in Asians after Jews in Israel and 2.5 times higher than that in neighboring countries like Iran and India, accounting for 34.6% of female cancers. The Pakistani population is deficient in information regarding breast cancer etiology and epidemiology, but efforts done so far had suggested consanguinity as a major risk factor for frequent mutations leading to breast cancer and has also shed light on genetic origins in different ethnic groups within Pakistan. World-wide research efforts on different ethnicities have enhanced our understanding of genetic predisposition to breast cancer but despite these discoveries, 75% of the familial risk of breast cancer remains unexplained, highlighting the fact that the majority of breast cancer susceptibility genes remain unidentified. For this purpose Pakistani population provides a strong genetic pool to elucidate the genetic etiology of breast cancer because of cousin marriages. In this review, we describe the known breast cancer predisposition factors found in the local Pakistani population and the epidemiological research work done to emphasize the importance of exploring factors/variants contributing to breast cance, in order to prevent, cure and decrease its incidence in our country.

Epidemiology, major risk factors and genetic predisposition for breast cancer in the Pakistani population.

The incidence of cancer is increasing worldwide, but the biochemical mechanisms for the occurrence of cancer is not fully understood, and there is no cure for advanced tumors. Defects of posttranslational modifications of proteins are linked to a number of important diseases, such as cancer. This review will update our knowledge on the critical role of posttranscriptional regulation of phosphatase and tensin homolog (PTEN) and its activities and the functional impact on cancer behaviors. PTEN is a tumor suppressor gene that occupies a key position in regulating cell growth, proliferation, apoptosis, mobility, signal transduction, and other crucial cellular processes. The activity and function of PTEN are regulated by coordinated epigenetic, transcriptional, posttranscriptional, and posttranslational modifications. In particular, PTEN is subject to phosphorylation, ubiquitylation, somoylation, acetylation, and active site oxidation. Posttranslational modifications of PTEN can dynamically change its activity and function. Deficiency in the posttranslational regulation of PTEN leads to abnormal cell proliferation, apoptosis, migration, and adhesion, which are associated with cancer initiation, progression, and metastasis. With increasing information on how PTEN is regulated by multiple mechanisms and networked proteins, its exact role in cancer initiation, growth, and metastasis will be revealed. PTEN and its functionally related proteins may represent useful targets for the discovery of new anticancer drugs, and gene therapy and the therapeutic potentials should be fully explored.

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Posttranslational regulation of phosphatase and tensin homolog (PTEN) and its functional impact on cancer behaviors.

Arsenic trioxide (As2O3), an effective agent against acute promyelocytic leukemia, has been reported to inhibit the viability of solid tumors cell lines recently The detailed molecular mechanism underlying the As2O3-induced inactivation of the cdc2 and possible functional role of PTEN in the observed G2/M arrest has yet to be elucidated Here, we assessed the role of PTEN in regulation of As2O3-mediated G2/M cell cycle arrest in Hepatocellular carcinoma cell lines (HepG2 and SMMC7721) After 24 h following treatment, As2O3 induced a concentration-dependent accumulation of cells in the G2/M phase of the cell cycle The sustained G2/M arrest by As2O3 is associated with decreased cdc2 protein and increased phospho-cdc2(Tyr15) As2O3 treatment increased Wee1 levels and decreased phospho-Wee1(642) Moreover, As2O3 substantially decreased the Ser473 and Thr308 phosphorylation of Akt and upregulated PTEN expression Downregulation of PTEN by siRNA in As2O3-treated cells increased phospho-Wee1(Ser642) while decreased phospho-cdc2(Tyr15), resulting in decreased the G2/M cell cycle arrest Therefore, induction of G2/M cell cycle arrest by As2O3 involved upregulation of PTEN J Cell Biochem 113: 3528–3535, 2012 © 2012 Wiley Periodicals, Inc

Arsenic trioxide induces G2/M arrest in hepatocellular carcinoma cells by increasing the tumor suppressor PTEN expression

The PTEN gene, a candidate tumor suppressor, is one of the more commonly inactivated and extensively studied genes in cancer. However, few data are available about the role of germ line mutations of this gene in sporadic breast cancer cases. The purpose of this study was to determine extent of involvement of this gene in breast cancer in Pakistan. To test the hypothesis that genetic variations of PTEN play a role in the etiology of breast cancer, a population based case-control study was conducted in 350 breast cancer patients along 400 healthy controls. After extracting DNA from blood, the whole coding sequence of PTEN along with intron/exon boundaries was genotyped by polymerase chain reaction-single stranded conformational polymorphism. Sequencing analysis revealed nineteen different types of mutations in different regions of PTEN (in exon 2, 4, 5, 6, 7 and splicing sites of intron 2 and 4 and also in the 3' UTR region), including 3 silent, 8 missense, 2 frame shift and 6 splice site variations. Among the observed variations in this study, three missense mutations have already been reported i.e. 319G>A (Asp106Asn), 389G>A (Arg129Gln) and 482G>A (Arg160Lys) in different populations. The present results suggest that a wide range of germline PTEN mutations may play a role in the pathogenesis of breast cancer.

Genetic changes in the PTEN gene and their association with breast cancer in Pakistan.

Mutations at specific hotspots in non-coding regions of ADGRG6, PLEKHS1, WDR74, TBC1D12 and LEPROTL1 frequently occur in bladder cancer (BC). These mutations could function as biomarkers for the non-invasive detection of BC but this remains largely unexplored. Massively-parallel sequencing of non-coding hotspots was applied to 884 urine cell pellet DNAs: 591 from haematuria clinic patients (165 BCs, 426 non-BCs) and 293 from non-muscle invasive BC surveillance patients (29 with recurrence). Urine samples from 142 non-BC haematuria clinic patients were used to optimise variant calling. Non-coding mutations are readily detectable in the urine of BC patients and undetectable, or present at much lower frequencies, in the absence of BC. The mutations can be used to detect incident BC with 66% sensitivity (95% CI 58-75) at 92% specificity (95% CI 88-95) and recurrent disease with 55% sensitivity (95% CI 36-74) at 85% specificity (95% CI 80-89%) using a 2% variant allele frequency threshold. In the NMIBC surveillance setting, the detection of non-coding mutations in urine in the absence of clinically detectable disease was associated with an increased relative risk of future recurrence (RR = 4.62 (95% CI 3.75-5.48)). As urinary biomarkers, non-coding hotspot mutations behave similarly to driver mutations in BC-associated genes and could be included in biomarker panels for BC detection. 

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Saniya Hafeez

Papers

Genetic changes in the PTEN gene and their association with breast cancer in Pakistan.

Properties of non-coding mutation hotspots as urinary biomarkers for bladder cancer detection