Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2023 | Month : June | Volume : 17 | Issue : 6 | Page : ZE01 - ZE04 Full Version

Unveiling the Enigma of the Phosphatase and Tensinogen Gene in Cancer and its Potential Role in Oral Cancer- A Narrative Review


Published: June 1, 2023 | DOI: https://doi.org/10.7860/JCDR/2023/63221.18000
Bindiya Narang, Revati Deshmukh, Sangeeta Palaskar, Anirudha Bartake, Swati Patil

1. Professor, Department of Oral Pathology, Sinhgad Dental College and Hospital, Pune, Maharashtra, India. 2. Professor and Head, Department of Oral Pathology, Bharti Vidyapeeth Dental College and Hospital, Pune, Maharashtra, India. 3. Professor, Department of Oral Pathology, Sinhgad Dental College and Hospital, Pune, Maharashtra, India. 4. Professor, Department of Oral Pathology, Sinhgad Dental College and Hospital, Pune, Maharashtra, India. 5. Assistant Professor, Department of Oral Pathology, Sinhgad Dental College and Hospital, Pune, Maharashtra, India.

Correspondence Address :
Bindiya Narang,
Eowaterfront, Kharadi, Pune-411014, Maharashtra, India.
E-mail: drbindiya@yahoo.co.in

Abstract

Phosphatase and Tensin Homolog (PTEN) is a tumour suppressor gene that plays a vital role in the normal cell cycle. PTEN acts on the cell via the phosphatidyl-inositol-3-kinase pathway which is involved in the process of cell growth, differentiation, migration, and survival. PTEN is most frequently inactivated in human cancers, because of genetic alterations or transcriptional/post-transcriptional modifications. Literature search was done using the keywords “PTEN in cancer” and “PTEN in Oral Cancer” using Pubmed as the database. This article briefly discusses the multiple features of the PTEN gene and its significance in cancer for improving the understanding of the biology of oral carcinogenesis and the potential for future research in this field.

Keywords

Malignancy, Oral neoplasms, Phosphatidyl-inositol-3-kinase pathway, Tumour supressor gene

Cancer is a significant health issue worldwide and is responsible for a considerable number of deaths. Oral cancer, in particular, is highly prevalent and alarming, especially in India. Despite the vast research conducted on this condition, it remains a major cause of mortality. The incidence and prevalence of oral cancer in the present era have increased from the past due to shifts in lifestyle, thereby changing the environmental factors, the treatment modalities, diagnostic methods, and last but not least demographics. Around 77,000 new cases and 52,000 deaths are reported annually in India, which is approximately one-fourth of global incidences (1). Oral cancer now occurs in younger individuals as compared to earlier days (2). Amongst all Oral Squamous cell Carcinoma (OSCC) is the most prevalent type and has multifactorial aetiology encompassing genetic changes and epigenetic factors (3). It can affect any part of the oral cavity. Chemotherapy, radiotherapy, and surgical management are considered the standard treatments for oral cancer. However, despite the advancements in these treatment modalities, the mortality rate for oral cancer remains high. This could be due to several factors, such as late diagnosis, advanced stage of cancer, metastasis to other parts of the body, and poor response to treatment (4). Additionally, the side-effects of these treatments can also contribute to the mortality rate, such as weakened immune system, infection, and other complications. Therefore, it is important to continue research and development in the field of oral cancer treatment to improve the outcomes for patients and decrease the mortality rate. Targeted therapy, which is a highlight in many other cancers such as breast cancer, is still ongoing research in OSCC (5).

Oral cancers in human beings have a multitude of genetic changes in every tumour. There are numerous genes involved in the cell kinetics of the human body. Change or mutation in any one of the genes can lead to carcinogenesis. One such gene is a tumour suppressor gene- PTEN. PTEN gene also named Mutated in Multiple Advanced Cancers 1 (MMAC), is the most common “tumour suppressor gene” which is spotted on chromosome ‘10q23’ (6),(7). It tunes the “AKT signaling” pathway which represses apoptosis and advances cell survival. The main function of PTEN is to obstruct this AKT signaling pathway which in turn will suppress cell survival and promote apoptosis. Thus, PTEN will act as a watch guard against the cells which are damaged and need to be removed from the cell cycle (8). PTEN downregulation is seen in various other cancers such as cancers of breast, prostate, colorectum due to polymorphisms. Gene silencing due to genetic changes and epigenetic modifications of the PTEN gene has also been observed in a group of cancers. Methylation in the promoter region of the PTEN is frequently been observed in cancer of breast, cervix, endometrium, colorectum and brain (9),(10),(11).

Thus, PTEN methylation may be used as a biomarker for cancer as the loss of PTEN gene is associated with carcinogenesis. PTEN also acts as an essential factor in response to insulin and other growth factors in the cells and is also seen as associated with the process of aging. Somatic PTEN polymorphisms have also been observed to date in many sporadic tumours like breast cancer, prostate cancer and lung cancer (12). PTEN also has a role in repair mechanism and maintaining the balance of the genome. Studies have witnessed that, PTEN is phosphorylated on Tyrosin (Tyr) 240 in response to De-oxyribonucleic Acid (DNA) damage [13,14]. It then binds to chromatin and enhances the binding of Radiation Absorbed Dose (RAD) 51 to promote DNA repair. This explains the reason why downregulation of PTEN results in resistance to radiotherapy (15).

Pathways of PTEN

PTEN was first detected in 1997 (16). PTEN deciphers a “dual-specificity protein phosphatase” which is involved in controlling the “phosphatidylinositol 3-kinase (PI3K)/AKT” signaling pathway. PTEN affects cell proliferation by activating G1 arrest in the cell cycle, obstructing cell migration, and persuading cell apoptosis (17). It is among the three important signaling pathways associated with Receptor Tyrosine Kinase (RTK) activity, along with the protein kinase C and Ras/MAPK pathway. The binding of RTK with the specific receptors activates PI3K pathway and generates an important product-phosphatidylinositol 3,4,5-trisphosphate (PIP3). PTEN is an important regulator of the cellular PI (phosphoinositide) 3-kinase signaling pathway. This AKT pathway regulates the activation of class I “PI 3-kinase” enzymes, activating the second messenger PtdIns P3 (phosphatidylinositol 3,4,5-trisphosphate) from its precursor PtdIns P2 (phosphatidylinositol 4,5-bisphosphate). PtdIns P3 activates downstream signaling by means of a range of effector proteins, including the proto-oncogene product Protein Kinase B (PKB)/Akt, which can identify this lipid and bind it selectively. PTEN antagonises PI 3-kinase signaling by dephosphorylating the 3-position of the inositol ring of PtdIns (3,4,5) P3 and thus inactivating downstream signaling of the pathway (17),(18).

The phosphorylation activates serine-threonine PKB, which is also known as AKT, through 3-phosphoinositide-dependent kinase-1. AKT phosphorylation is seen at the T308 position of tyrosine and S473 of serine, causing an immense increase in enzymatic activity. This further activates AKT protein which initiates the transcription of the gene encoding for various proteins such as those involved in glucose metabolism (GLUT4 and hexokinase), protein synthesis (mTOR and ribosomal protein S6), and cell survival (Bcl-2 and Bad), which are involved in many cellular processes.

As a negative regulator of PI3K/Akt/mTOR signaling, and having a tumour-suppressor role, the downregulation of PTEN gene expression can inflict the malignant behaviour of cancer. Increased malignancy of cells after deletion of PTEN is due to unattended activation of the PI3K/Akt signaling pathway. Thus, reduced expression of PTEN can result in carcinogenesis and uncontrolled proliferation and metastasis of cancer cells (Table/Fig 1) (17).

According to the literature, six important mechanisms are essential for the initiation and progression of cancer. Evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, tissue invasion and metastasis, and limitless replicative potential (19). It is noticed that PtdIns(3,4,5) P3 signaling appears to be involved in the regulation of almost all of these mechanisms. One reason for the importance of PTEN in cellular signaling and its tumour suppressor status in many of the tumour types is the lack of functional dissipation. Although other PtdIns(3,4,5)P3 phosphatases have been identified, there are no widely expressed PTEN homologues, and it appears that in many (or most) cell types, PTEN activity has a strong influence on both basal and stimulated PtdIns(3,4,5)P3 levels (13).

With a decrease in PTEN levels, the cancer cells continue to proliferate with more potential to escape the apoptosis. This can be due to the inhibition of glycolysis by PTEN which is involved in the promoted growth of cancer cells (13).

Structure of PTEN

PTEN is a well-known tumour-suppressor gene. There are nine exons on the PTEN gene, and it enciphers a 403-aminoacid protein that has both protein and lipid phosphatase roles and has five functional domains: a) N-terminal phosphatidylinositol 4-5-diphosphate (PIP2)-binding domain; b) phosphatase domain; c) membrane-targeting C2 domain; d) C-terminal tail; and e) a PDZ binding motif. The activities of the gene are controlled by a group of C-terminal phosphorylation (phospho-C-tail) events on Ser380, Thr382, Thr383 and Ser385 by a group of C-terminal phosphorylation (phospho-C-tail) (20),(21).

Role of PTEN in Cancer

PTEN, known as an important tumour suppresser oncogene, involved in the process of cell cycle, growth, and survival of the cells 2in various tumours, was found by various research teams (21),(22). A decrease in the function of PTEN in cancer can be attributed to decreased synthesis of protein, increased protein breakdown, and post-translational modifications. The function of the most common type i.e., the wild type is regulated by its post-translational modifications. This is due to variation in its localisation at the sub-cellular level, interaction between the proteins, and/or phosphatase activity, irrespective of PTEN accumulation (22),(23).

It has been observed that complete absence of the PTEN gene expression is dangerous during development at the embryonic level, and partial suppression results in cancer. PTEN gene has also been studied in the prognosis of cancer. The prognostic significance has been mentioned to be involved in cancer of uterus, breast, prostate, lung, and plasma cells (malignant melanoma) (24),(25),(26),(27),(28). PTEN gene mutation has also been observed in head and neck cancers, especially oral cancers. Shin KH et al., observed point mutation frequency in PTEN gene in approx., 4.65% of cases from which four were due to missense mutations and one due to frame shift mutation in four oral cancers (29).

Shah S et al., on Indian Population has reported that intronic deletions were seen in PTEN gene in three cases, without any statistically significant correlation with gender, tumour size, stage, or grade. In this study, the coding region of the gene did not show any mutations (30). The survival time was reported to be less in PTEN negative individuals as compared to PTEN positive individuals protein deregulation is more commonly seen in advanced grades and stages of the tumour by Lee JI et al., (7).

PTEN function dysruption is frequently seen in prostate cancer. Many studies have suggested the significant role of PTEN in prostate cancer as a tumour suppressor oncogene (31),(32). It is also significantly correlated with increased expression of B-cell lymphoma-2 (Bcl-2) in glioblastomas (33) and prostate cancer (34). It has been observed that that loss of PTEN function increases with the stage of the disease and lymph node metastasis. Such patients with loss of PTEN function in cases of prostate cancer show poor prognosis (31). The simplest way in such cases is to restore the PTEN function. Increasing the dose of PTEN artificially in prostate cancer patients, it is possible to reduce the burden of the tumour by its tumour suppressive activity, thereby drastically improving the prognosis. Therapeutic induction of PTEN in prostate cancer patients is under study. In-vitro studies have been successful wherein nanoparticle-assisted PTEN protein has been introduced in the prostate cancer cell lines which resulted in a decrease in viability of cells (32).

In breast cancer, (primary and secondary tumours), loss of PTEN activity results in limitless transduction of P13K signal. Almost 40%-50% of breast cancer patients have reported a Loss Of Heterozygosity (LOH) at the PTEN loci and about 5%-10% of breast cancer patients reported a loss of PTEN function. The most common type of mutation reported in such cases was the frameshift mutations. Studies have been done in mouse mammary glands which stated that the loss of function of PTEN results in induction of initiation and malignant transformation of breast tumours (20),(26). Polymorphism of PTEN gene at the germline level have also been reported in hereditary syndromes associated with cancer like Cowden’s syndrome, thereby increasing the risk for other malignancies like breast cancer, endometrium cancer, thyroid cancer and colorectum cancer. Tumour growth and progression have been reduced by introducing PTEN messenger Ribonucleic Acid (RNA) in tumour models (20).

PTEN in Oral Cancer

Though the genetic alteration of PTEN is seldom found in head and neck cancer, it is commonly associated with oral cancer. Gao F et al., reported that the disease-free survival time was more for individuals who showed a positive PTEN expression in tongue cancer. This implies that the PTEN gene is linked with prognosis of OSCC (35). Research done on correlation between PTEN gene polymorphism, deleted on chromosome 10 (PTEN) and (OSCC) in the Chinese population showed a positive association between the two (36). The intronic region of the tyrosine phosphatase domain of the PTEN gene showed 5% somatic mutational frequency. Kurasawa Y et al., conducted a study on correlation of PTEN gene in OSCC individuals as well as in the cell lines, observed statistically significant difference between the expression of OSCC cases and healthy individuals. PTEN expression was decreased in OSCC cases also, mRNA expression using Reverse Trancriptase-Polymerase Chain Reaction (RT-PCR) showed a downregulation in the PTEN gene expression in OSCC cases. But no genetic changes in the PTEN gene in the cell lines could be found. Hence, it was concluded that the decreased expression of PTEN gene could be because of epigenetic factors and is an important factor in carcinogenesis of OSCC (37).

PTEN as a Diagnostic and Prognostic Biomarker for Cancer

Cancer is heterogeneous in nature with varied presentation and progress. Hence, it is essential to identify biomarkers for predictive and diagnostic purposes. PTEN, apart from its prognostic indicator potential, can also help in predicting body’s response to various anti-tumour agents. It is also possible that PTEN can also affect tumour micro-environment and immune infiltrate in cancers directly or indirectly along with changing the behaviour of cancer cells (36). These interactions may result in a permissive or anti-permissive tumour microenvironment. Hence, PTEN plays a vital role to control the overall result of these interactions. Thus, PTEN can be considered as a biomarker for prognostic and diagnostic purposes in various cancers. Though studies have been done concluding the prognostic and diagnostic role as a biomarker, the regulation of this gene is extremely complex, and is difficult to ascertain the absence of the gene or loss of the function of PTEN (36),(37).

Immunohistochemistry and immunofluorescence are commonly used to evaluate PTEN protein expression while fluorescent in-situ hybridisation and next generation sequencing) are used to assess the PTEN genomic status (32).

PTEN and Chemotherapy

PTEN deficiency has been reported in chemotherapy-resistant tumours. For example pre-clinical trials have documented the role of PTEN in treatment modules in individual’s resistance to the chemotherapeutic drug, Trastuzumab which is frequently used in targeted therapy. This could be attributed to activation of proto-oncogene non-receptor tyrosine protein kinase by de-phosphorylation. It has also been observed that in cases of prostate cancer relapse of the tumour was more common in patients with PTEN loss when compared to those with intact PTEN (38),(39).

Studies done on pre-clinical models have suggested that loss of PTEN can cause increased expression of Programmed Cell Death Ligand 1 (PD-L1), which reaffirms the importance of PTEN in modulating the response to immune checkpoint inhibition [40,41]. Artificially increasing PTEN expression by overcoming its transcriptional and post-transcriptional repression is also under investigation and can serve as a remedial avenue for therapeutic intervention to increase PTEN activity. Demethylating agents which are able to restore PTEN expression can also provide a beneficial therapeutic approach for patients with PTEN silencing (40).

PTEN and Immunotherapy

Literature search shows that rearrangement of the immune system of an individual in favour of an anti-cancer microenvironment can show a tremendous improvement in the treatment of various hematological cancers and solid tumours [40,42]. Immunotherapy has been considered a novel method in the treatment of cancer in many cancers showing a remarkable improvement in survival rate. But this success has been observed in research clinical trials, not every patient responds in the same way. This could be due to the reason that various signaling pathways are involved in the process of carcinogenesis (43).

One such pathway is the P13K signaling pathway. This pathway may bring about a difference in the tumour microenvironment which in turn can change the immune response in the treatment of cancer. For a decade a literature has proven the function of PTEN in various cancers in animals [40,44]. A study done by Peng W et al., concluded that loss of PTEN causes an increase in expression of immune-suppression cytokines which in turn results in a decrease in T cell infiltration and apoptosis resulting in decreased T cell-mediated cell death. This reaffirms the association of the role of PTEN in tumour microenvironment and immunity (45). Thus, changing the level of PTEN in cancer patients will open new potential implications for immunotherapy of cancer (46).

Conclusion

Molecular studies have proven the role of PTEN in various cancers and its restoration has a profound effect in the treatment of cancer. More such clinical trials need to be conducted in all types of cancer. PTEN can thus be used as a predictive and prognostic marker. It has good potential in targeted therapy as well. Thus unrevealing the various aspects of PTEN gene suggests that there is immense potential for future research on the therapeutic aspects of this gene.

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Tables and Figures
[Table / Fig - 1]
DOI and Others

DOI: 10.7860/JCDR/2023/63221.18000

Date of Submission: Feb 02, 2023
Date of Peer Review: Mar 25, 2023
Date of Acceptance: Apr 17, 2023
Date of Publishing: Jun 01, 2023

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Feb 04, 2023
• Manual Googling: Apr 12, 2023
• iThenticate Software: Apr 15, 2023 (10%)

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