Sequencing of the human genome has revealed that ∼20,000 traditional genes encode protein molecules, occupying just 2% of the total genetic landscape (Salzberg, 2018; Viggiano, 2022). The remaining genome consists of non-protein-coding regions, including numerous ‘RNA only’ genes, among which there is a large but diverse group called long non-coding RNAs or lncRNAs for short (Elkon and Agami, 2017; Dietlein et al., 2022; Paloviita and Vuoristo, 2022). Subsequent analyses have shown that lncRNAs fulfill various regulatory roles in healthy and cancerous tissues (Geng et al., 2018; Bi et al., 2019; Farzaneh et al., 2022a; Farzaneh et al., 2022b; Farzaneh et al., 2022c; Nasrolahi et al., 2022). As such, their expression and function are often altered in disease states (Kleinbrink et al., 2021; Yang et al., 2021; Anderson and Anderson, 2022; Dietlein et al., 2022; Erdogan et al., 2022) with selected examples now being used as diagnostic markers for various diseases including cancers (Li et al., 2019; Deng and Zou, 2022; Najafi et al., 2022; Zhang et al., 2022). Among these, one particular lncRNA called LINC-PINT (P53 Induced long Non-coding Transcript) appears exceptional because of its universalized functions and relationship to the famous tumor suppressor gene P53 (He et al., 2021; Bukhari et al., 2022). Indeed, like P53, LINC-PINT was first proposed as an oncogene but later revealed as a tumor suppressor in human cancers.

LINC-PINT contributes to a variety of biological processes impacting cancer cell growth and metastasis, with involvement in processes ranging from DNA damage responses to cell senescence and apoptosis (Simchovitz et al., 2020; He et al., 2021; Wang et al., 2021; Xiang et al., 2021; Zhang et al., 2021; Bukhari et al., 2022). It has also been shown to be an essential regulator of many other diseases, including autoimmune diseases (Wang and Zhao, 2020; Salviano-Silva et al., 2021). These functions arise through interactions affecting epigenetic regulation or direct interactions with other biomolecules, including proteins and other lncRNAs (Xu et al., 2019; Bukhari et al., 2022). Some alternatively spliced variants of LINC-PINT also act as host transcripts for circular RNA (circRNA) generation, and these can serve as sources for the translation of short functional peptides (Xiang et al., 2021). More than 100 alternatively spliced variants of LINC-PINT have been identified (Bukhari et al., 2022). Still, to date, only a few of these have been thoroughly studied—a feature earning the name PINTology to describe the current and future studies involving LINC-PINT.

Cancer cells exhibit variability formally termed tumor heterogeneity, and this is a well-known explanation behind the failure of cancer therapy where resistant cells selectively survive repeated drug treatments (Brutovsky, 2022; Mahinfar et al., 2022). Contributing to this problem is also the lack of suitable diagnostic, therapeutic and prognostic biomarkers (Najafi, 2022). Hence, optimizing treatment outcomes for any disease is only possible with full knowledge of the underlying mechanisms. In this regard, recent studies involving lncRNAs have substantially contributed to understanding the cancer (Li et al., 2022b; Singh et al., 2022; Zhong et al., 2022). However, exploiting the potential of lncRNAs as biomarkers and therapeutic targets is just the beginning (Mirzaei et al., 2022). For example, lncRNAs associated with immune checkpoints (Li et al., 2022a; Jiang et al., 2022; Wen et al., 2022) have been used as disease biomarkers in the new wave of cancer immunotherapy that is currently revolutionizing oncology practice (Figure 1A). Nevertheless, small successes in the clinical setting are expected to help build confidence in lncRNAs as biomarkers and produce the momentum needed for their broader applications.

Although the tumor-suppressive function and downregulation of LINC-PINT in different cancers have been thoroughly established (He et al., 2021; Bukhari et al., 2022), its clinical use remains extremely limited. It is interesting to note that many of the vital protein targets of LINC-PINT involved in cell cycle regulation are already widely used in the diagnostic setting (Caputo et al., 2014; Xu et al., 2019). Furthermore, some of these are cancer treatments with inhibitors of LINC-PINT’s targets now being used in treating melanoma (George et al., 2019). As a starting point, the most appropriate clinical application of LINC-PINT would be as a diagnostic or predictive marker for specific cancers such as esophageal cancer, where LINC-PINT has been associated with cancer recurrence (Zhang et al., 2019; Rong et al., 2021). Indeed, the abnormal expression of LINC-PINT reflects many vital predictors of cancer outcomes such as lymph node metastasis, tumor size, and differentiation status (Figure 1A). Notably, the levels of LINC-PINT released by tumor cells into the blood could also be used to measure therapeutic responses, as specific anti-cancer drugs induce the re-expression of LINC-PINT. Other positive associations with neuropathy along with pemphigus foliaceous, diabetes, and arthritis may also be exploited, suggesting LINC-PINT as a multifaceted target for cancers and other diseases.

We assessed the survival of patients and immune function associated with LINC-PINT expression in COAD tissues from the TCGA resource. Notably, patients whose tumors expressed low levels of LINC-PINT showed better overall and disease-free survival (Figure 1B, C). Subsequently, LINC-PINT showed a strong association with immune indicators, Tumor Mutation Burden (TMB), and Microsatellite Instability (MSI) in the COAD tumor microenvironment. COAD cases exhibiting higher expression of LINC-PINT had significantly lower immune scores, including stromal, immune, and ESTIMATE scores (Figure 1D), meaning that patients with low expression of LINC-PINT have a better immune response. Additionally, TMB and MSI have been used as prognostic markers for many cancers, especially for those receiving immunotherapy (Rizzo et al., 2021); thus, these can be used as predictive biomarkers for the efficacy of immunotherapy. Patients with low expression of LINC-PINT showed significantly higher TMB and MSI scores (Figures 1E–G), reflecting that LINC-PINT may be used as a novel biomarker of immune checkpoint inhibitors (ICIs).

Compared to most lncRNAs, extensive literature exists for LINC-PINT, but a key question is whether this truly reflects most or, if not all, the underlying molecular mechanisms involved. In particular, the relationship between the functions of LINC-PINT in cancers versus non-malignant diseases needs to be better explored. For example, in viral hepatitis leading to liver cancer development, LINC-PINT foremost contributes to inflammation during viral infection and then later, to the pathogenic properties of the cancer cells (Khatun et al., 2021a; Khatun et al., 2021b), but whether the underlying processes involved are the same in both disease stages is not clear. Consequently, more intensive patient-based clinical studies are required to dissect these points. Furthermore, the large number of splice variants complicates this task, and it will be necessary to identify which variants share functions versus those that contribute to different functions. It is worth mentioning that at least one LINC-PINT variant produces small peptides, but this phenomenon’s frequency needs to be clarified. As functional products, these peptides may themselves serve as diagnostic molecules or treatment targets. It would be similarly valuable to ascertain more knowledge of the natural activators or inhibitors of LINC-PINT, which could be used to open potential new doors in cancer therapeutics. And to end on a sobering note, the number of lncRNA genes may rival or exceed the number of coding genes with LINC-PINT just one amongst thousands. However, there is the expectation that the pioneering studies involving LINC-PINT will provide important precedents for the clinical applications of lncRNAs.

LncRNAs are crucial regulators of various cellular pathways specifically cancer-associated pathways and use different mediators to function (Peng et al., 2017; Kopp and Mendell, 2018; Ali and Grote, 2020), while the majority of lncRNAs are functionally uncharacterized (Li et al., 2017; Lorenzi et al., 2021). Specifically, the regulation of lncRNAs occurs during specific occasions, such as development and cell growth (Sun et al., 2018). Mechanistically, lncRNAs bind with DNA, RNA, and proteins for transcriptional, post-transcriptional, and post-translational regulations (Schmitt et al., 2016; Hull et al., 2021; Yue et al., 2021). LncRNAs play vital roles in cancer initiation and progression or inhibition by affecting various pathways and expression of genes (Zhuo and Kang, 2017; Statello et al., 2021), showing that lncRNAs are either onco-suppressor or onco-promoter.

Similarly, LINC-PINT is a crucial lncRNA that mainly acts as an onco-suppressor in various cancers, but its clinical use is almost neglected. However, studies have suggested it as a potential biomarker for cancer prognosis (Ghafouri-Fard et al., 2021; He et al., 2021; Ghafouri-Fard et al., 2022). Through analysis of colon cancer data from the TCGA data, we determined an enticing relationship between LINC-PINT expression, prognosis and patients’ survival. Interestingly, patients with low expression of LINC-PINT showed better survival and significantly higher TMB and MSI scores together with better responses to chemotherapy, thus supporting the clinical importance of LINC-PINT, especially its use as a biomarker for monitoring responses to immunotherapy and chemotherapy.

It is now commonly known that lncRNAs are key players in cancer regulation, a feature that promotes their application as target-based therapies in cancer and other relevant diseases. Interestingly, this promise has now been realized with several RNA-based therapeutics being recently approved by the FDA although their integration into the healthcare system still requires extensive clinical trials. It is well known that LINC-PINT has universalized tumor suppressor functions and a relationship to the tumor suppressor gene TP53 and several LINC-PINT targets are commonly used in clinical practice (directly or indirectly). Based on these facets, LINC-PINT emerges as a priority target for studying the clinical potential of lncRNAs (PINTology), especially for cancer therapeutics. However, the direct application of LINC-PINT is still limited due to the lack of clinical trials and clinicians’ confidence. Nevertheless, the current evidence proposes applications as a diagnostic marker for cancer and several other diseases with alterations in LINC-PINT circulatory levels providing a readily accessible platform to develop appropriate tests.