Abstract

1 Introduction

Cancer, with high morbidity and mortality, has long been known as a primary life-threatening disease worldwide and imposes a huge economic and social burden on every country. (Sung et al., 2021) In recent years, the life expectancy of patients with cancer has greatly increased owing to the earlier detection and appropriate therapies. However, several cancer complications such as tumor metastasis, drug resistance, and cancer recurrence hinder the management of this disease and contribute to the high mortality associated with it. (Barik et al., 2021) Although traditionally most research about these processes has focused on the role of protein-coding RNAs (Slack and Chinnaiyan, 2019), recent efforts have focused on non-coding RNAs, which are now known to be regulatory molecules that mediate cellular processes and play an important role in tumorigenesis and cancer development. (Anastasiadou et al., 2018)

Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides and comprise the main category of non-coding RNAs (Palazzo and Koonin, 2020) According to the latest release of the database NONCODE, the number of human lncRNAs is approximately 170,000, which is much larger than that of protein-coding RNAs. (Derrien et al., 2012; Zhao et al., 2021) Most lncRNAs are transcribed by RNA polymerase II, and then are capped at the 5′ end, ploy A tail added at the 3′ end, and edited to form biologically functional lncRNAs. (Statello et al., 2021) According to classification based on function, lncRNAs can be divided into activating ncRNAs, competing endogenous RNA (ceRNAs), and precursors for shorter functional RNA. (St Laurent et al., 2015) Most lncRNAs act as ceRNAs. The “competitive endogenous RNA hypothesis,” which was put forward by Salmena et al., in 2011, proposes that lncRNAs regulate mRNA expression by targeting miRNAs through homologous miRNA response elements (MREs). By binding to MREs present in miRNAs, lncRNAs inactive them, a process known as the “molecular sponge effect”, suppressing the inhibitory effect of the targeted miRNA on mRNA expression. (Salmena et al., 2011) Numerous posterior studies have confirmed the lncRNA-miRNA-mRNA axis established by this hypothesis, as well as the role of this axis in tumor development.

Long intergenic non-coding RNA (lincRNA) is defined as ‘lncRNA not overlapping a protein-coding transcript’. (Ransohoff et al., 2018) LINC00467, a newly defined lincRNA, is located at Chromosome 1: 211,382,736-211,444,093 (GRCh38/hg38) with the length of 61,358 bases (www.genecards.org). Moreover, it encodes 28 different transcripts (www.ensembl.org). In addition to being upregulated in normal human testis and kidney tissues (Fagerberg et al., 2014), recent studies have confirmed that LINC00467 is overexpressed in various types of human tumor tissues and plays an important role in regulating gene transcription, tumor initiation, and progression.

In this review, we comprehensively summarize the different functional roles of the newly found LINC00467 in the progression of various cancers. LINC00467 mainly functions as a ceRNA and leads to the overexpression of relevant genes by sponging the corresponding miRNAs. Additionally, we present the clinical significance of LINC00467 in several human cancers and discuss its potential clinical application as an early diagnostic and prognostic biomarker and novel therapeutic target.

2 Function of lncRNAs

Proteins are universally acknowledged to be the basis of life. However, “non-protein-coding” is not the same as being useless. Mounting studies have demonstrated the indispensable and promising role of lncRNAs in many diseases. Herein, we summarized the main functional mechanisms of lncRNAs in the following paragraphs. Moreover, we made a figure to illustrate the function of lncRNAs more graphically. (Figure 1).

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FIGURE 1

Functional mechanisms of lncRNAs. lncRNAs can act as miRNAs sponges (A), binding with proteins (B), and templates for polypeptide translation (C). Abbreviations: lncRNA, Long non-coding RNA. miRNAs, microRNAs. RNP complex, ribonucleoprotein complex.

3 Clinical Significance of LINC00467 in Various Human Cancers

Various studies have investigated the expression of LINC00467 in different tumor tissues and corresponding controls (mostly adjacent non-malignant tissues). All studies (except that by Cai et al. (2019)) indicated that the expression of LINC00467 was upregulated in a variety of cancer tissues compared to the control group. In addition, numerous studies of different tumor types have assessed the prognosis of patients with high or low LINC00467 expression level and its association with prognostic features such as TNM (Tumor, Node, Metastasis) staging, cell differentiation, disease-free survival, and overall survival. Patients with high expression of LINC00467 tend to have advanced TNM stage, poorer cell differentiation, and shorter disease-free survival and overall survival. The details of relevant studies have been summarized in Table 1.

4 Molecular Mechanism of LINC00467 in Diverse Human Cancers

To date, dozens of studies have reported the effects of LINC00467 in various human cancer cell lines, including its impact on tumor cell proliferation, invasion, migration, and apoptosis (Table 2). In the following sections, we elaborate on the functional roles and molecular mechanism of LINC00467 in various cancers. Additionally, another figure was made to illustrate these molecular mechanisms of LINC00467. (Figure 2)

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FIGURE 2

Molecular mechanisms of LINC00467 in various tumors. Abbreviations: NB, Neuroblastoma; NSCLC, Non-small cell lung cancer; OS, Osteosarcoma; ESCC, Esophageal squamous cell carcinoma; AML, Acute Myeloid Leukemia; LUAD, Lung adenocarcinoma; CRC, Colorectal cancer; HNSCC, Head and neck squamous cell carcinoma; BCa, Bladder Cancer; CC, Cervical cancer; TGCT, Testicular germ cell tumor; GC, Gastric cancer; PCa, Prostate cancer; HCC, Hepatocellular carcinoma; BRCA, Breast Cancer; GBM, Glioblastoma.

5 Discussion

Recent studies have shown that LINC00467 overexpression is associated with numerous diseases, especially with the progression of various types of tumors. However, the role of LINC00467 in HCC is controversial. In addition, several studies have confirmed that high expression of LINC00467 is associated with poor prognosis in various tumor types. Functional experiments on cancer cells showed that LINC00467 could promote the proliferation, invasion, migration, and inhibition of apoptosis of tumor cells, while silencing LINC00467 exerted the opposite effects. However, owing to the different sample sizes and procedures of each study, the results are non-concluding, and a larger study or multicentre joint studies are needed to further verify these conclusions. Additionally, studying LINC00467 expression levels in human blood or other body fluids would be beneficial for evaluating its clinical application as a promising biomarker for the early diagnosis and prognosis of various diseases. Moreover, silencing LINC00467 could be a suitable therapeutic strategy, but more studies are needed to verify this. In vivo studies of LINC00467 with cell-derived and patient-derived xenograft animal models are required to further assess the role of LINC00467 in tumor progression, avoid the limitations of in vitro studies, and test new treatment options. However, some of the studies referred to in this paper, such as those conducted for OS, CRC, TGCT, GC, glioma, esophageal cancer, and HNSCC, were performed only in vitro without further in vivo validation of their findings.

LINC00467 has been demonstrated to function through diverse regulatory mechanisms, mainly acting as a ceRNA of a series of miRNAs, including miR-339, miR-494-3p, miR-125A-3p, miR-4779, miR-7978, miR-20b-5p, miR-107, miR-509-3p, miR-18a-5p, miR-9-5p, miR-217, miR-451A, miR-138-5p, miR-485-5p, miR-299-5p, miR-1285-3p, miR-7-5p, miR-200a, miR-339-3p, and miR-485-5p. By sponging these miRNAs, LINC00467 alters the expression level of downstream genes and influences cell signalling pathways. Central signalling cascades have been found among the pathways regulated by LINC00467; for example, the Wnt/B-catenin pathway in LUAD. However, a few studies failed to fully elucidate the mechanism of action of LINC00467 in some diseases. For example, a study found that LINC00467 could competingly bind with miR-451a, but its downstream gene was not studied. (Bai et al., 2020) Additionally, Bo et al. reported that LINC00467 promotes TGCT cell invasion and migration by activating AKT3. However, the detailed regulatory mechanism between LINC00467 and AKT3 is not illustrated. (Bo et al., 2021) Herein, we expect more comprehensive and in-depth studies to advance the clinical application of LINC00467 in the future.

It is worth noting that studies on HCC have shown that LINC00467 expression is higher in HCC tissues than in controls (Jiang et al., 2020; Wang et al., 2020; Zheng et al., 2020) However, Cai et al. (2019) reported the opposite result in their clinical samples. Furthermore, they found that LINC00467 expression in HCC tissues with metastasis was lower than that in non-metastatic tissues. This contradiction needs to be assessed by further validation with more clinical samples of HCC. Meanwhile, several studies reported that LINC00467 plays a carcinogenic role in HCC by sponging miR-18a-5p or miR-509-3p (Zheng et al., 2020; Li W. et al., 2021), inhibiting NR4A3 (Wang et al., 2020), and binding to IGF2BP3. (Jiang et al., 2020) Cai et al. (2019) studied the LINC00467/miR-9-5p/PPARA axis and concluded that LINC00467 exerts a tumor-suppressive effect in HCC tissues. If the data is real, this contradiction on HCC indicates that LINC00467 plays different roles depending on the cell type.

In addition to regulating the expression level of downstream genes, LINC00467 also functions as a protein-coding RNA, as it encodes several short peptides. Before Andrews and Rothnagel (2014) and Bazzini et al. (2014) reported that ncRNAs could encode hundreds of functional micro peptides, lncRNAs had long been regarded as “transcriptional noise”. Soon afterward, Anderson et al. (2015) found a novel micro peptide myoregulin (MLN), encoded by a lncRNA, plays an important role in regulating skeletal muscle physiology. Similarly, in CRC, LINC00467 can encode a short peptide ASAP, which promotes CRC cell proliferation. Although current studies on LINC00467 and other lncRNAs mainly focus on their interaction with miRNA or proteins, further investigation into the function of these micro peptides encoded by short open reading frames is needed.

Exosomes are a subtype of extracellular vesicles with a diameter of 40–150 nm, secreted by almost all types of living cells (Cocucci and Meldolesi, 2015) An increasing number of studies have confirmed that exosomes are responsible for many biological functions as they transport a large number of functional units, such as DNA, RNA, and proteins. Data from the GEO databases shows that one of the LINC00467 transcripts (NONCODE ID: NONHSAT225914.1) is expressed in exosomes of some samples, such as those from tuberculosis patient serum and HepG2s (Hepatocellular Carcinoma Cell Line Exosomes). Further studies should be conducted to determine the role of exosome-mediated transport of LINC00467 in various diseases.

In this review, the latest research progress on LINC00467 is summarized, and its biological mechanisms and clinical application value in various tumors are detailed. The described studies highlight that LINC00467 plays a remarkable role as an oncogene. Further research on LINC00467 and its mechanism of action may contribute to its use for disease diagnosis, targeted therapy, and prognostic evaluation in the future.

References