ReviewDual role of G-quadruplex in translocation renal cell carcinoma: Exploring plausible Cancer therapeutic innovation
Introduction
Cancer marks as the second leading cause of death globally, affecting about 9.6 million deaths in 2018. About 1 in 6 deaths occur due to cancer worldwide. Previous studies have shown that the accumulation of several genetic alterations directly or indirectly controls cancer while types of such alterations are widely variable which makes cancer a highly comprehensive condition. Genetic alteration in turns causes oncogene activation, loss of tumor suppressor gene, truncated or fusion gene generation with oncogenic potential mediating altered cellular functions which induces a normal cell into a cancerous cell. Chromosomal aberration is a central facet of cancer cells. The exact mechanism behind such alteration is still not understood which further poses a continued challenge.
Renal Cell Carcinoma (RCC) is very rare and aggressive. Worldwide RCC is the ninth leading cause of death among kidney cancers, whose chances of incidence increases annually. According to the American Cancer Society report 2019, globally 73,820 adults (44,120 men and 29,700 women) were approximately diagnosed with kidney cancer in the United States only. This disease is rarely found in younger-onset (<45 years) but the average age of diagnosis is 64 years [American cancer society 2019]. RCC originates from epithelium tissues of renal tubules which could be characterized by clinical and histological phenotypes and detected by abdominal computerized tomography (CT) and ultrasounds. RCC categorized in 3 types i.e. ccRCC: Clear Cell RCC, a most common (70–80%), pRCC: Papillary RCC, 15–20% & cRCC: Chromophobe RCC, the rarest (approx 5%) [1].These three RCC subtypes have different Histological features (Fig. 1). Late presentation and resistance to hormonal therapy, chemotherapy, and radiotherapy make RCC poor prognostication. Currently, there is no clinically proven therapy for RCC; therefore, new therapeutic strategies are needed in improving the therapeutic approach for RCC [2]. The occurrence of RCC in males is 25% higher than females showing distinct sex differences in RCC incidence, suggests the possible role for sex hormones & their receptors in RCC progression [3]. RCC has been reported as a hormone-related condition. Several hormone signaling pathways were outlined in RCC as some steroid hormone and hormone receptors such as - gonadotropin-releasing hormone (GnRH), estrogen receptors (ER), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), glucocorticoid receptors (GR), androgen receptors (AR), etc. were overexpressed in RCC while corticotrophin-releasing hormone, Vitamin D, and progesterone receptors are down-regulated in different subtypes of RCC [4]. These findings prompt to investigate the role of hormone and their receptors with great interest. Essentially targeting such hormone signaling pathways could be a progressive step towards RCC prevention research. Targeting the sex hormone receptor and their pathways possibly reveal the role of hormonal signaling behind the sexual disparities in RCC. Further experimental investigation for the role of steroid hormone in RCC may justify the molecular basis behind the hormone-related etiology in RCC.
Kidney carcinoma was sub-classified in Translocation renal cell carcinoma (tRCC) by WHO in 2004. tRCC has been associated with Xp11.2 translocation that is controlled by a novel promoter of the TFE3 gene, known as the TFE3 transcription factor gene. This cancer subgroup found to be at young-onset mostly [5]. Not only RCC, but TFE3 fusion protein (the result of translocation) associated with Alveolar Soft Part sarcoma also falls in the same category. TFE3 as a transcription factor is an important protein in normal genetic behavior while fusion variants of TFE3 alter the genetic expression.
Section snippets
TFE3
TFE3 (Transcription Factor E3) is one of the members of the microphthalmia Family (MiT) transcription factor, which binds and activates transcription of genes containing E-box sequences (5’-CANNTG-3′) in their promoter. The cytogenetic location of TFE3 is Xp11.23; the genomic view is represented in Fig. 2.
TFE3 protein consists of transcription activation domain (AD), basic helix-loop-helix domain (b-HLH), and a leucine zipper domain. b-HLH and leucine zipper domain of TFE3 form protein
G-quadruplex
G-quadruplex (G4) is a non-B-form of DNA secondary structure, composed of the four-stranded helical structure formed by hoogsteen hydrogen base pairing within repetitive 4 guanine tracts in DNA or RNA that undergoes either intra and inter-molecular folding to generate square planer structure G-quartet which further stacked on top of one another and forms four-stranded helical conformations of G4. This conformation stabilizes by the presence of cation in the center of each pair of G-quartet. The
Putative G-quadruplex sequences (PQS) prediction in target genes
Sequences of genes ASPSCR1 (NG_030375.2), PRCC (NG_008138.1), and TFE3 (NG_016297.2) was retrieved from NCBI database and SFPQ (ENSG00000116560) retrieved from Ensemble database, were analyzed for putative G4 sequence prediction by online tool QGRS Mapper, a web-based server. Parameters of QGRS Mapper analysis are Max length: 30, Min G-group: 3, loop size 0 to 36. QGRS Mapper predicted several PQS in all 4 gene sequences; among them, some sequences (both exon and intron regions) with high
Conclusion
Xp11 Chromosomal translocation is the cytogenetic characterization of translocation renal cell carcinoma, a predominant kidney cancer whose incidence rate and mortality rate rises continuously. While several therapies were offered for renal cell carcinoma it still remains insufficient because of the high chemo-resistant property of RCC with side effects of drugs. Temsirolimus & sunitinib are some drugs discovered against Xp11.2 translocation but their mode of action is still unknown. In the
Future perspective
Association of G4 with several diseases, including cancers, offer potential opportunity for targeted therapeutic intervention. Stabilization of such G4 structure within fusion transcript as well as their destabilization at translocation break-point supposed to be inhibiting fusion gene expression and translocation, respectively that could be a potential future direction for cancer research. The Discovery of novel G4 stabilizers and destabilizers with high efficiency should improve the
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We acknowledge Dr. Chandana Basu Mallick, DBT Welcome Trust Fellow, Centre for Genetic Disorders, BHU for her critical reading and feedback on this manuscript. We also acknowledge the contributions of the various research groups towards the expansion of the G-quadruplex work. We sincerely try to include and refer all the works relevant to this review; any inadvertent failing is highly regretted.
This research did not receive any specific grant from funding agencies in the public, commercial, or
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