Encyclopedia
Please note this is a comparison between Version 1 by Najah Nassif and Version 2 by Camila Xu.
The PTEN gene is an important and well-characterised tumour suppressor, known to be altered in many cancer types. Interestingly, the effect of the loss or mutation of PTEN is not dichotomous, and small changes in PTEN cellular levels can promote cancer development.
- PTEN
- PTENP1
- ceRNA networks
- microRNAs
1. Introduction
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN), also known as mutated in multiple advanced cancers 1 (MMAC1) and TGFß-regulated and epithelial cell-enriched phosphatase 1 (TEP-1) [1][2][3][1,2,3], is a well-known tumour suppressor gene located on chromosome 10q23.31 [2]. The gene and its protein product play a vital role in cell proliferation, migration, and survival [2][4][5][6][7][2,4,5,6,7]. As an antagonist of phosphoinositide 3-kinase (PI3K), PTEN dephosphorylates its substrate PIP3 to PIP2, thereby negatively regulating the pro-proliferative and anti-apoptotic PI3K/Akt pathway to maintain cellular homeostasis [8][9][8,9]. The regulation of PTEN cellular levels is critical in the negative modulation of tumorigenesis with disruption of PTEN signalling leading to significant cellular changes. Interestingly, subtle decreases in cellular levels of PTEN can result in malignancy and tight regulation of the expression, function, and cellular half-life of PTEN, at the transcriptional, post-transcriptional, and post-translational levels is necessary in the prevention of carcinogenesis [10][11][10,11]. PTEN is frequently mutated and/or deleted in the inherited PTEN hamartoma tumour syndromes (PHTS) [12][13][12,13] and multiple sporadic human malignancies, including those from the brain, breast, prostate [1], endometrium [14], skin (melanoma) [15], and colon [6].
Less well-known regulatory mechanisms of PTEN with emerging importance include the PTEN–miRNA–PTENP1 axis, which has been shown to play a critical role in the fine tuning of PTEN regulation and cellular integrity. PTENP1 is a processed pseudogene of PTEN termed the phosphatase and tensin homolog pseudogene 1 (PTENp1, PTENpg1, PTENP1, PTH2, and ψPTEN), which is located on 9p13 (Gene ID: 101243555) [16][17][18][16,17,18]. This pseudogene is transcribed to produce sense and antisense transcripts with the sense transcript showing high sequence similarity with the PTEN transcript; however, unlike PTEN, this transcript is not translated to produce a protein [19]. Although PTENP1 protein is undetected in cells, when transcribed in vitro as a fusion protein, the product is viable and has comparable phosphatase activity to the wild-type PTEN [19]. The sense and antisense long non-coding RNAs (lncRNA) produced from PTENP1 are important in the modulation of PTEN expression at the transcriptional and post-transcriptional levels, respectively. The PTENP1 sense transcript (PTENP1-S), acting as a competitive endogenous RNA (ceRNA) of PTEN, leads to alterations in PTEN cellular abundance. The characteristics of this PTEN pseudogene lncRNA include similarities in their microRNA (miRNA) binding sites, and as such, PTENP1 can act as a decoy or ‘sponge’, competing for miRNAs that target PTEN. Disruption of the PTEN–miRNA–PTENP1 axis and ceRNA networks in carcinogenic progression is contemporary and is an exciting area in the discovery of regulatory mechanisms that are altered in cancer. In addition to its regulation of PTEN expression, PTENP1 is able to act as a tumour suppressor independent of its PTEN regulatory function as described in a recent review of the role of PTENP1 in human disorders with a focus on its tumour suppressor functionality [20].
2. PTEN and Cancer: From Mutations to a Continuum Model of Tumorigenesis
Germline and somatic mutation of PTEN is known to contribute to many cancers, highlighting the importance of this tumour suppressor in cancer initiation, progression, and metastasis. Germline mutations of PTEN are the cause of four autosomal dominant inherited syndromes: Cowden syndrome (CS) [21], Bannayan–Riley–Ruvalcaba syndrome (BRRS) [22][23][22,23], Proteus syndrome (PS), and PS-like syndrome [24], which share common features, including the development of multiple benign hamartomas, and are all classified under the umbrella term of the PTEN hamartoma tumour syndromes (PTHSs) [12][13][12,13]. PTHS patients have an increased lifetime risk of developing specific malignancies, mainly breast cancer (approximately 80%) [12][13][12,13], thyroid cancer (approximately 30%) [12][13][12,13], renal cell carcinoma (approximately 34%) [13], endometrial cancer (approximately 28%) [13], and colorectal cancers (approximately 9%) [13]. In individual PHTS patients exhibiting clinical phenotypes, PTEN germline mutations are reported in 25-85% of CS patients [21][25][26][21,25,26], 60% of BRRS [21][22][25][27][21,22,25,27], up to 20% of PS [28], and between 50 and 67% of PS-like syndrome patients [24]. Interestingly, germline PTEN mutations are also associated with a subset of patients with autistic behaviour and extreme macrocephaly [29]. Somatic mutations of PTEN are frequently associated with tumorigenesis with somatic alterations of PTEN being described in over 50% of cancers of various types [30]. PTEN somatic mutations are most prevalent in prostate cancer [31], endometrial cancer [32], melanoma [33][34][33,34], non-small-cell lung cancer [35][36][35,36], kidney [37], breast cancer [38], and glioblastoma [39]. PTEN somatic alterations include the complete loss or inactivation of one allele (functional haploinsufficiency) due to point mutations and/or deletions and/or epigenetic silencing through hypermethylation of the PTEN promoter, which is characteristic of some advanced and metastatic cancers [1][4][1,4]. Deletion of both alleles of PTEN occurs at a lower incidence but is seen mostly in metastatic breast cancer, melanomas, and glioblastomas [1][4][40][1,4,40]. In contrast, a recent study showed that patients with high PTEN expression levels in endometrial cancer had low tumour malignancy, decreased cancer cell proliferation and a better prognosis [41]. There are different mechanisms of PTEN loss or inactivation, with some being more prevalent in specific tumour types (Table 1) [30][42][43][30,42,43].Table 1.
Mechanism and frequency (%) of
PTEN
loss in various cancer types.
| Cancer Type | Mutation | Deletion | Loss of Protein | Promoter Methylation | ||||
|---|---|---|---|---|---|---|---|---|
| Glioblastoma | 30% | [2][3][42][44][45][46][2,3,42,44,45,46] | 78% | [44][45][46][47][44,45,46,47] | 65% | [48] | 6% | [49] |
| Breast | 3% | [42][50][51][42,50,51] | 27% | [38][52][38,52] | 40% | [42] | 35% | [53][54][53,54] |
| Prostate | 13% | [55][56][57][58][55,56,57,58] | 51% | [56][57][58][56,57,58] | 54% | [55][56][57][58][55,56,57,58] | <5% | [42][59][60][61][42,59,60,61] |
| Colorectal | 7% | [6]6[42][62][63][,4264,62],63[65,64][66][,65,66] | 8.7% | [42][62][63][42,62,63] | 40% | [67] | 17% | [68] |
| Lung | 8% | [42] | 34% | [42] | 56% | [42] | 38% | [69] |
| Endometrial | 41% | [14][42][70][14,42,70] | 48% | [14][42][70][14,42,70] | 45% | [14][41][14,41] | 19% | [42][71][42,71] |
| Ovarian | 16% | [42][43][72][73][74][75][76][42,43,72,73,74,75,76] | 48% | [42][43][72][73][74][75][76][42,43,72,73,74,75,76] | 44% | [42][43][72][73][74][75][76][42,43,72,73,74,75,76] | 10% | [42][77][42,77] |
Note: Where multiple references are provided, the frequencies of mutation, deletion, and promoter methylation are an approximate average across the relevant publications.
The effect of the loss or mutation of PTEN is not dichotomous, and subtle changes in PTEN cellular levels have been shown to lead to deleterious consequences relating to tumour incidence, penetrance, and aggressiveness in several epithelial cancers [11][78][11,78]. In the hypomorphic transgenic Pten mouse, it has been shown that in susceptible organs such as the prostate, PTEN protein expression levels need to reach dramatically low levels (reduced by 70% compared to normal levels) to initiate tumorigenesis, however, in the mammary glands, a more subtle reduction (reduced by 20% compared to normal levels) can initiate tumorigenesis [78]. Thus, PTEN does not follow the ‘two-hit’ paradigm or stepwise model of tumour suppressor gene function but rather presents a new continuum model of tumorigenesis whereby tumorigenesis occurs in an incremental dose-dependent manner [11][78][11,78]. This has been evidenced in gastric cancer, where PTEN expression was shown to gradually decrease with increasing gastric cancer progression [79].
