Review articleLong non-coding RNA TINCR as potential biomarker and therapeutic target for cancer
Graphical abstract
Introduction
Cancer initiation, promotion, progression, and metastasis involve a series of fundamental heterogeneous steps, resulting in challenges for its detection and treatment [1,2]. Additionally, several factors are associated with cancer etiology, such as genetic mutations, environmental conditions, and alterations in the expression levels of the molecules involved in cellular signaling pathways and maintenance of genome stability [3]. Interestingly, more than 90% of the human genome is transcribed into non-coding RNAs (ncRNAs), while less than 2% of the genome is transcribed and translated into proteins [4,5]. Long non-coding RNAs (lncRNAs), defined as RNA molecules of >200 nucleotides in length, do not code for annotated proteins, yet their abnormal expression has been shown to play essential roles in several cancer-associated signaling molecules/pathways such as Notch, mTOR, NF-kb, and Wnt/β-catenin [6,7]. Because of their roles in multiple signaling pathways, the dysregulation of lncRNA expression is thought to contribute to the development of various types of cancers as ascertained from their oncogenic or tumor-suppressive properties [[8], [9], [10]]. Furthermore, lncRNA expression has been correlated with many clinicopathological features of cancer patients, including age, gender, lymph node metastasis, Ki-67 levels, histological grade, tumor size, and tumor node metastasis stage [11,12].
Tissue differentiation-induced non-coding RNA (TINCR), also known as placenta-specific protein 2 (PLAC2), is a lncRNA located on chromosome 19p13.3 in humans, and is abnormally expressed in many cancers (Fig. 1) [13]. Recently, the role of TINCR has been investigated in association with cancers, including breast [14,15], lung [16,17], hepatocellular carcinoma [18], esophageal [19], colon [[20], [21], [22], [23]], bladder [24], prostate [25], gastric [[26], [27], [28], [29]], and oral squamous cell carcinoma [30] (Table 1). It was determined that overexpression of TINCR promoted cell proliferation and metastasis via activation of the Wnt/β-catenin signaling pathway in oral squamous cell carcinoma [30]. In contrast, TINCR inhibited apoptosis by targeting the Krupple Like Factor 2 (KLF4) gene in gastric cancer [29]. Additionally, similar inferences were elucidated stating a significant association of TINCR levels, via sponging of miR-7-5p, and regulating the PI3K/Akt/mTOR signaling pathways contributing to colorectal carcinogenesis [21].
As TINCR has been implicated in the pathogenesis of many cancers, in this review, we focus on the mechanistic roles of TINCR in contributing to oncogenesis by cancer type. We also discuss the clinical utility of TINCR as a novel approach for cancer diagnosis, prognosis, and as a potential therapeutic target.
Section snippets
Breast cancer
Breast cancer is the most prevalent type of malignancy among women worldwide, and the 5-year survival of tumor node metastasis (TNM) stage-IV has been estimated to be less than 20% [9,31]. Multiple factors correlate with high breast cancer incidence such as female gender, infertility issues, obesity, nulliparity, hormonal treatment for menopause, exposure to environmental ionizing radiation, excessive tobacco and alcohol use, diet, and genetic dysfunction (e.g., BRCA1 and BRCA2 mutations) [[32]
Lung cancer
Lung cancer is the leading cause of cancer-related death worldwide, with 5-year median survival rates of less than 15% [43]. Earlier studies showed that a variety of lncRNAs are closely associated with the development and progression of lung cancer [44]. To better understand the correlation of TINCR with the occurrence and development of lung cancer, Liu et al. found significant downregulation (~2.9-fold) of TINCR expression in lung cancer tissue samples (n = 45), compared to healthy lung
Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide [49]. Recent studies have demonstrated the diagnostic and prognostic potential of miRNAs and lncRNAs as a novel biomarkers for the timely, noninvasive diagnosis of HCC [50]. Additionally, Tian et al. measured the expression levels of TINCR by qRT-PCR in 248 human HCC samples and their matched adjacent healthy tissues, and found significant upregulation (~8.7-fold) of TINCR in HCC tissues (Table 1)
Esophageal cancer
Based on histopathological data, esophageal cancer (EC) is often classified into two subtypes; esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC). To elucidate the underlying mechanisms involved in the initiation and progression of EC, several lncRNAs were studied, such as POU3F3 [51], SPRY4-IT1 [52], FOXCUT [53] and HOTAIR [19,54]. Similarly, TINCR, as a recently discovered regulatory molecule has been studied for the diagnosis and treatment of ESCC. Xu et al. analyzed the
Colorectal cancer
Despite recent advances in the available treatments, the 5-year survival rate for metastatic colorectal cancer (CRC) patients remains critically low (~10%) [57]. Studies have reported that several lncRNAs play critical roles in the regulation of pathways involved in CRC [57]. In this regard, Zhang et al. observed a downregulated profile of TINCR (~1.5-fold) in CRC tissue when compared to adjacently paired healthy non-tumor tissues obtained from 44 CRC patients [58] (Table 1). Additionally, TINCR
Bladder cancer
Bladder cancer (BCa) accounts for ~95% of urothelial carcinomas, making BCa the most malignant cancer of the urinary tract [68]. Global statistics show that over a million new cases and ~15,000 mortalities have been reported annually [69,70]. Despite recent advances in novel prognostic and diagnostic methods for BCa patients, frequent recurrence and metastasis persist [70]. Several studies have validated a significant correlation between BCa and dysregulation and various lncRNAs, such as H19 [
Prostate cancer
Major advances have been made in the development of novel prognostic biomarkers for prostate cancer (PCa), such as serum levels of prostate-specific antigen (PSA) and Gleason score (>7 for high-risk patients) [76,77]. However, despite these recent improvements, the overall survival rate of PCa patients is ~31% in the United States [78]. Therefore, there is a compelling need to develop contemporary technology with enhanced diagnostic, prognostic, and therapeutic potential for PCa patients. In
Gastric cancer
Gastric cancer (GC) has been identified as the fifth most commonly diagnosed cancer type, and the third leading cause of cancer death worldwide [81]. A lack of early signs and symptoms leads to a poor prognosis, with a devastating 5-survival rate of only ~25% [82]. Unfortunately, genetic factors and distinct mechanisms contributing to the pathogenesis of GC remain largely unknown. However, recent studies have demonstrated a correlation between GC and TINCR. For instance, Chen et al. have
Oral squamous cell carcinoma
Despite recent advancements in novel diagnostic and prognostic techniques, early diagnosis of oral squamous cell carcinoma (OSCC) remains poor. Therefore, there is a need to discover new molecular markers for the early diagnosis of OSCC and/or serve as targets for therapy. LncRNAs can act as potential biomarkers and specific targets in the diagnosis and treatment of OSCC; for example, lncRNAs that have been identified as contributors of OSCC development include OIP5-AS1 [84], TUG1 [85], MEG3 [86
Conclusions and perspectives
Studies in the recent past have demonstrated the oncogenic and tumor suppressing potential of TINCR and its associated impact on various hallmarks of cancer such as cell survival and proliferation, invasion and metastasis, apoptosis, and on drug responsiveness. Interestingly, TINCR has been reported to have tumor suppressor and/or oncogenic functions in cells. This may be accounted for a variety of factors, including tissue-specific functions, cell type, and/or genetic and epigenetic
Funding
AJ is thankful to the Department of Biotechnology, India for providing grant (6242-P30/RGCB/PMD/DBT/AKJN/2015), the Indian Council of Medical Research (5/13/81/2013-NCD-III), and an NIH/NCI grant to KMV (CA093729). Uttam Sharma is thankful to the Department of Science and Technology for DST-INSPIRE fellowship (IF180680).
Author contributions
US, AM and AJ conceived the idea. US, TSB, and AM wrote the majority of the manuscript. NP, Vivek, DD, AG, US composed the figures and table. Critical revisions were made by, HST, KMV, and AJ. All authors read and approved the final manuscript.
Ethical approval
Since it's a review article, therefore, this article does not contain any studies with human participants or animals performed by any of the authors.
Declaration of competing interest
The authors declare no conflict of interest.
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