|Year : 2020 | Volume
| Issue : 2 | Page : 113-115
Nucleostemin: A new trailblazer in oral squamous cell carcinoma – A brief review
Sayani Shome1, Rudra Prasad Chatterjee2, Sanchita Kundu1, Sanjeet Kumar Das2
1 Department of Oral and Maxillofacial Pathology, Guru Nanak Institute of Dental Sciences and Research, Kolkata, West Bengal, India
2 Department of Oral and Maxillofacial Pathology, Guru Nanak Institute of Dental Sciences and Research; Department of Oral and Dental Science, JIS University, Kolkata, West Bengal, India
|Date of Submission||11-Jan-2020|
|Date of Acceptance||18-Feb-2020|
|Date of Web Publication||21-May-2020|
Department of Oral and Maxillofacial Pathology, Guru Nanak Institute of Dental Sciences and Research, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Nucleostemin (NS) is a guanine nucleotide binding protein like 3 (GNLP 3) found in the nucleolus in neuroepithelial stem cells, embryonic stem cells and in cancer stem cells. It is observed to be an initiator for uncontrolled cellular proliferation that is responsible for cancer progression by interaction with p53, mouse double minute 2 (MDM2) and cell-cycle.
Keywords: Cell cycle, malignant transformation, nucleostemin, P53
|How to cite this article:|
Shome S, Chatterjee RP, Kundu S, Das SK. Nucleostemin: A new trailblazer in oral squamous cell carcinoma – A brief review. Indian J Dent Sci 2020;12:113-5
|How to cite this URL:|
Shome S, Chatterjee RP, Kundu S, Das SK. Nucleostemin: A new trailblazer in oral squamous cell carcinoma – A brief review. Indian J Dent Sci [serial online] 2020 [cited 2020 May 28];12:113-5. Available from: http://www.ijds.in/text.asp?2020/12/2/113/284669
| Introduction|| |
Cancer is defined as “complex disease in genes that encodes protein that controls cell-cycle, cell-motility, cell-survival and angiogenesis” by the World Health Organization. Oral cancer, precisely “Oral Squamous Cell Carcinoma (OSCC),” is considered as the sixth most common malignancy worldwide exhibiting an alarmingly higher rate of morbidity and mortality. Molecular and genetic mutation prevails as the most promising etiology in oral carcinogenesis besides exogenous factors. Despite the multifactorial nature of OSCC, the exact cause is still unresolved, thus compromising its prognosis. The emergence of cancer stem cells (CSCs) is in the forefront of cancer pathogenesis since decades culminating into a new conjecture of diagnostic and prognostic targets. CSC possesses some identical characters to that of adult tissue stem cells and its eminent attributes are well established in OSCC as well. Epidermal stem cells have been designated as one of the key factors of the aggressive front in OSCC. Nucleostemin (NS) is a newly discovered nucleolar GTP-binding protein which plays an important role in pre-rRNA processing, synthesis of the ribosome, and maintenance of genome integrity. It is responsible for regulating stemness of a cell and was described in murine stem cells earlier. This nucleotide-binding protein-like 3 (GNLP 3) suggested its high expression predominantly in neuroepithelial stem cells in the central nervous system, embryonic stem cells, primitive stem cells in bone marrow, and in CSC. NS is reported to bind with p53 protein that regulates cell cycle and influences cell proliferation. The presence of NS in malignant cells aims to delineate its role in uncontrolled proliferation by inhibiting p53 tumor-suppressive activity due to the upregulation of mouse double-minute 2 (MDM2), a protein destined for the destruction of p53.,
| P53-”guardian of Genome”|| |
The widely known tumor suppressor gene p53 acclaimed as the ”Guardian of Genome” is located on chromosome 17p. 13.1 and it is the most common target for genetic alteration in various human tumors. It acts as a “molecular policeman” that prevents the propagation of genetically damaged cell through the cell cycle. p53 mediates cell-cycle arrest by inactivating MDM2 in response to DNA damage (by hypoxia, cellular damage, radiation etc.,) which is a primordial response in checking uncontrolled cell proliferation which is a hallmark of cancer cell growth. Almost 50% of human tumors contain mutations in this gene where p53 allele becomes unable to recognize cell damage and cannot trigger programmed cell death (apoptosis). Thus, with the repression of p53, DNA damage goes unrepaired and mutations accumulate in dividing cells leading to malignant transformation. Diminution of p53-dependent cell-cycle arrest and apoptosis coupled with the activity of NS are of supreme importance pertaining to neoplastic growth. Higher expression of NS is found in the testis (Tsai and McKay, 2002), whereas guanine nucleotidebinding protein like 3 like (GNL3 L) is preferentially expressed in the cerebellum and forebrain (Yoshida R et al. 2011)., GNL3 L is expressed in less quantity in the undifferentiated neural stem cells (NSCs) compared to differentiated progeny (Tsai, unpublished data), while NS is predominantly expressed by early neuroepithelial precursors (Tsai and McKay, 2002). NS is involved in the propagation of cell cycle, particularly in G2-M and G1-S transition. The decline of NS remains consistent with cell-cycle exit and experimentally has been demonstrated by the incorporation of small-interfering RNA (SiRNA) that blocks cell cycle through NS inhibition. Logical association among NS, cell cycle, and p53 is thus necessary to interpret the proper way of malignant cell proliferation and autonomous growth potential of CSC.
| Nucleostemin–interrelationship among P53, Mouse Double-Minute 2, and Cell Cycle|| |
According to RYL Tsai et al., mammalian NS is designated as a potent cell proliferation marker. It was first discovered as a gene that is more abruptly expressed by embryonic neural stem cell than their progeny. He had described that different studies using siRNA, reverse transcriptase–polymerase chain reaction (RT-PCR), and gene knockdown had suggested that NS is functionally linked to provoke inactivation of p53 by inducing MDM2. Several studies demonstrated the indispensable function of NS for survival and continuous proliferation of p53 – null normal or cancer cell. Tumor suppressor gene p53 responds to diverse genotoxic stresses and maintains cell-cycle arrest, apoptosis, senescence, and DNA repair. In unstressed cells, p53 is found in low level because of MDM2 hyperactivity which is an ubiquitin ligase. MDM2 inhibits normal p53 function by proteasome-ubiquitin pathway. NS-depleted cells have found to be deprived of cell proliferative capacity. According to Huang G et al., both under and overexpression of NS activates p53 through MDM2 inhibition in an aberrant manner; on one side, overexpressed NS stabilized p53 causing cellcycle arrest, and on the contrary, depletion of NS by siRNA induced p53 activity via enhancement of ribosomal protein binding by MDM2. Signal that promotes cell proliferation is delineated by translocation of NS between nucleolar and nucleoplasmic compartments. The prime signal for the trafficking of NS is immense GTP activity which regulates cell cycle and recent discovery from RYL Tsai's laboratory states function of NS in genome stabilization. The role of NS in ribosome synthesis also has been elaborated by Romanova et al. in 2009 and RY Tsai in 2014 who described the depletion of 60S ribosome in HeLa cells where NS gene was silenced. Cell lines that are deficient of NS shows impaired survival due to halt in G2-M checkpoint of mitosis. The blockade of cell cycle is one of the primary reparative responses in the way of malignant transformation as it can check abundant cell proliferation which is a prerequisite of any tumor microenvironment.
| Nucleostemin – Role in the Pathogenesis of Oral Squamous Cell Carcinoma|| |
Normal oropharyngeal and laryngeal epithelium exhibit NS-positive nucleoli in both basal and suprabasal cells. The role of NS in ribosome was previously highlighted in various molecular processes perpetuating its expression in neoplastic oral epithelium. NS has its approved expression in rat NSCs (Tsai and McKay, 2002) and in different types of cancer cell lines such as renal cancer and esophageal cancer (Fan et al., 2006; Nakajima et al., 2012). Few studies have explored the significance of NS in head-and-neck carcinoma, including OSCC (Cada et al., 2007). Neoplastic oral tissue associated with proliferation in OSCC cell lines have already revealed the presence of NS (Yoshida et al., 2014). One of the signaling pathways for the tumor invasion encompasses the signal transducer and activator of transcription 3 (STAT3) (Devarajan and Huang, 2009). It has been induced in cancer metastasis by transcriptionally regulating the expression of genes that mitigate cell kinetics such as cell proliferation, cell survival, invasion, angiogenesis, and tumor immune evasion (Huang, 2007). STAT3 is known to be activated by many cytokines, growth factors, and oncogenic proteins, and its overexpression corresponds to high-grade OSCC with worse prognosis (Shinriki et al., 2009; Macha et al., 2011). A link between NS and the STAT3 signaling pathway is still a mysterious field that needs to be unveiled more. Different studies have exhibited NS on the malignant progression of OSCC where two NS overexpressing OSCC cell lines have revealed enhanced cellular proliferation and invasion of the cells via the activation of STAT3 signaling. Moreover, strong immune positivity of NS in OSCC tissue samples is proved to have worse prognosis with advanced Primary Tumor size-Nodal status-Distant metastasis (TNM) staging. Although an expression of NS is not dependent on the proliferation status of neoplastic cells, NS-positive nucleoli are found to be greater in dimension compared to a normal one. NS expression in the mRNA and protein in OSCC cell line has been identified in various experiments by RT-PCR, Western blot technique, and immunohistochemistry. Depletion and overexpression of this NS protein result in cell-cycle arrest through p53-dependent and p53-independent manner being manifested as a double-edged sword, but the exact mechanism is still unclear. NS expression is generally downregulated in the early stages of differentiation before cell exits from the cell-cycle, and these initial observations suggest that NS is involved in multipotency of stem cells in the regulation of cancer pathogenesis. Thus, the role of NS in OSCC progression has been depicted to us through various pioneer studies leaving open questions regarding its prognostic and therapeutic considerations.
| Conclusion|| |
NS being a cell proliferation marker has an immense importance in embryonic stem cell propagation as well as in carcinogenesis. Researches on its dynamic role in cellular proliferation are still going on. From the comprehensive knowledge of NS in the progression of head and neck cancer, it is expected to reveal newer clues to combat this deadly disease.
We are indebted to Prof. Dr. R R Paul, Prof. Dr. Mousumi Pal, Prof. Dr. Sk. Abdul Mahmud, Dr. Neha Shah and Dr. Swagata Gayen and the entire Department of Oral and Maxillofacial Pathology, GNIDSR, for all the academic and relentless technical support for publication of this review article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization International Agency for Research on Cancer. Vol. 88. Lyon, France; 2006.
Dhanuthai K, Rojanawatsirivej S, Thosaporn W, Kintarak S, Subarnbhesaj A, Darling M, et al
. Oral cancer: A multicenter study. Med Oral Patol Oral Cir Bucal 2018;23:e23-9.
Cada Z, Boucek J, Dvoranková B, Chovanec M, Plzák J, Kodets R, et al
. Nucleostemin expression in squamous cell carcinoma of the head and neck. Anticancer Res 2007;27:3279-84.
Yoshida R, Nakayama H, Nagata M, Hirosue A, Tanaka T, Kawahara K, et al
. Overexpression of nucleostemin contributes to an advanced malignant phenotype and a poor prognosis in oral squamous cell carcinoma. Br J Cancer 2014;111:2308-15.
Tsai RY, McKay RD. A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev 2002;16:2991-3003.
Yoshida R, Fujimoto T, Kudoh S, Nagata M, Nakayama H, Shinohara M, et al
. Nucleostemin affects the proliferation but not differentiation of oral squamous cell carcinoma cells. Cancer Sci 2011;102:1418-23.
Huang G, Meng L, Tsai RY. p53 Configures the G2/M Arrest Response of Nucleostemin-Deficient Cells. Cell Death Discov 2015;1:pii: 15060.
Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 8th
ed. India; Saunders Elsevier; 2011. p. 2902.
Dai MS, Sun XX, Lu H. Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2. Mol Cell Biol 2008;28:4365-76.
Tsai RY, Meng L. Nucleostemin: A latecomer with new tricks. Int J Biochem Cell Biol 2009;41:2122-4.
Tsai RY. Turning a new page on nucleostemin and self-renewal. J Cell Sci 2014;127:3885-91.
Ross MH, Pawlina W. Histology A Text and Atlas. 7th
ed. China; Wolters Kluwer; 2016. p. 80.