A review on the role of LINC00511 in cancer

Long Intergenic Non-Protein Coding RNA 511 (LINC00511) is an RNA gene being mostly associated with lung cancer. Further assessments have shown dysregulation of this lncRNA in a variety of cancers. LINC00511 has interactions with hsa-miR-29b-3p, hsa-miR-765, hsa-mir-150, miR-1231, TFAP2A-AS2, hsa-miR-185-3p, hsa-miR-29b-1-5p, hsa-miR-29c-3p, RAD51-AS1 and EZH2. A number of transcription factors have been identified that regulate expression of LINC00511. The current narrative review summarizes the role of LINC00511 in different cancers with an especial focus on its prognostic impact in human cancers.


Introduction
Long non-coding RNAs (lncRNAs) are widely expressed transcripts with essential roles in gene regulation. Based on the results of the Human GENCODE project, the number of lncRNA genes in the human genome is estimated to surpass 16,000 (Fang et al., 2018). These transcripts embrace lncRNAs transcribed by RNA polymerase II, gene-overlapping antisense transcripts as well as lncRNAs from intergenic regions (lincRNAs) (Ghafouri-Fard et al., 2020;Ghafouri-Fard et al., 2021;Statello et al., 2021). Typically, lncRNAs have a 7-methyl guanosine cap at the 5′end and a polyadenylated tail at the 3′ends. Moreover, lncRNAs are spliced in a similar manner to mRNAs (Statello et al., 2021). However, several RNA polymerase II-transcribed lncRNAs are incompetently processed and are held in the nuclear compartment (Statello et al., 2021). LncRNAs interact with DNA, RNA and proteins. Through these interactions, lncRNAs influence chromatin structure and function, affect the assembly of nuclear bodies, change the stability and expression of mRNAs within the cytoplasm and regulate signaling pathways (Statello et al., 2021;Hussen et al., 2022). In comparison with mRNA promoters, lincRNA promoters have been found to be devoid of transcription factor binding sites, but having binding sites for a number of specific factors such as GATA and FOS (Melé et al., 2017).
Long Intergenic Non-Protein Coding RNA 511 (LINC00511) is an RNA gene being mostly associated with lung cancer. This lncRNA is encoded on chr17:72,290,091-72,640,472 (GRCh38/ hg38), minus strand. Notably, more than 100 alternatively splice variants have been recognized for LINC00511. Except for two variants with retained introns (LINC00511-279 with 3766 bp and LINC00511-278 with 508 bp), other are affiliated with lncRNA group of transcripts (https://asia. ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000227036; r=17:72290091-OPEN ACCESS EDITED BY 72640472). This lncRNA has important roles in the development of cancers and can be used as a possible diagnostic and prognostic marker in cancer. Abnormal expression of LINC00511 in a wide array of malignancies potentiates it as a target for therapeutic interventions.
Based on DIANA-LncBase database (https://diana.e-ce.uth.gr/ lncbasev3) (Karagkouni et al., 2020), expression of LINC00511 in various tissues and cell types have been investigated. With medium and high TPM levels and in homosapiens, the highest level of expression

FIGURE 1
A graphical illustration of the oncogenic role that LINC00511 performs in the environment of the many types of cancer.

FIGURE 2
The carcinogenic role of LINC00511 in ER-negative tumorigenesis. ER insufficiency enhanced TFAP-2 activity at particular promoter regions, promoting LINC00511 expression. By interacting with EZH2 to attract PRC2 to regulate histone methylation, the ER-negative-associated LINC00511 repressed the expression of CDKN1B, assisting in the G1/S transition to maintain cellular growth. of LINC00511 is in prostate tissue and PC3 cell type along with cancer/ malignant category.
The current narrative review summarizes the role of LINC00511 in different cancers with an especial focus on its prognostic impact in human cancers.

LINC00511 in cancers
Several studies have reported dysregulation (mainly upregulation) of LINC00511 in different cancers. These studies have also identified miRNAs that are sponged by LINC00511.

Breast cancer
In breast cancer, LINC00511 has been found to be highly expressed in the clinical samples and its over-expression has been correlated with poor prognosis (Lu et al., 2018). Functional studies have shown that LINC00511 promotes proliferation, sphere-formation capacity, expression of stem factors and growth of breast tumors (Lu et al., 2018). From a mechanical point of view, LINC00511 acts as a molecular sponge for miR-185-3p to enhance expression of E2F1 protein. Besides, E2F1 binds with the promoter of Nanog gene and increases its expression ( Figure 1). Therefore, LINC00511/miR-185-3p/E2F1/ Nanog axis has been identified as an important route for induction of stemness and tumorigenesis in breast cancer (Lu et al., 2018). Another study in breast cancer has revealed more than 180 potential targets for LINC00511 through siRNA and RNA-seq assays. Bioinformatics analyses have shown relation between differently expressed genes and signaling pathways mediated by p38-α and p38-β. LINC00511 has been found to be mainly located in the cytoplasm regulating expression of MMP13 through sponging miR-150 . Expression of LINC00511 in breast cancer samples has been closely correlated with the presence of lymph node metastasis, greater tumor size and molecular subtypes of breast cancer. This lncRNA has been found to increase migratory potential and invasive ability of MDA-MB-231 and MCF-7 cells. Moreover, expression of LINC00511 has been shown to be increased by DNA hypomethylation. In turn, LINC00511 could promote expressions of Wnt10A, E2F2, TGFA, and MET and reduce sensitivity of breast cancer cells to Panobinostat (Liu et al., 2021a). LINC00511 can also influence the cytotoxic effects of paclitaxel on breast cancer cells through regulating miR-29c/CDK6 axis .
Another study in patients with breast cancer has reported upregulation of LINC00511 and miR-301a-3p in patients' blood parallel with downregulation of miR-185-3p (Mahmoud et al., 2021). Notably, LINC00511 expression has been increased in Frontiers in Genetics frontiersin.org early stages of breast cancer. Area under the reciever operating characteristic curves of LINC00511, miR-185-3p, and miR-301a-3p has been superior to classical tumor markers indicating the diagnostic values of these transcripts as molecular biomarkers in liquid biopsy. Moreover, expression of LINC00511 has been correlated with lymph node metastasis and advanced tumor grades (Mahmoud et al., 2021). Additionally, the sponging effect of LINC00511 on miR-185 has been shown to be involved in breast cancer recurrence and radioresistance via regulation of STXBP4 expression . In breast cancer cells, LINC00511 expression induced by TFAP-2 expression and directly affected by ER deficiency at the transcriptional level. Through its interaction with EZH2, LINC00511 has been shown to encourage tumor development and suppress apoptosis ( Figure 2) . Table 1 summarizes the results of studies regarding the role of this lncRNA in breast cancer.

Lung cancer
LINC00511 has ben shown to promote proliferation, invasive capacities, and migration of non-small cell lung cancer cells through regulating miR-625-5p/GSPT1 axis . Moreover, LINC00511 can promote progression of this type of cancer through binding to EZH2 and LSD1 and decreasing expression levels of LATS2 and KLF2 . Besides, this lncRNA has a role in induction of tumor recurrence in this type of cancer through sponging miR-98-5p and increasing expression of TGFBR1 . LINC00511 can also induce resistance of lung cancer cells to Frontiers in Genetics frontiersin.org cisplatin through sponging miR-625 and influencing expression of LRRC8E . Finally, this lncRNA exerts its oncogenic effects in lung cancer through binding to EZH2 and decaresing expression of p57 (Sun et al., 2016). Table 3 shows the role of LINC00511 in lung cancer.

Other types of cancers
Over-expression of LINC00511 has been reported in a variety of cancers including colorectal, pancreatic, liver, thyroid and other types of cancers (Table 4).

FIGURE 3
The impact of LINC00511 on survival of patients with different cancers.
Frontiers in Genetics frontiersin.org

Impact of LINC00511 dysregulation on clinical outcome of patients with cancers
We investigated the survival rate caused by LINC00511 in different cancers using ualcan database (Chandrashekar et al., 2017). This database performs survival analysis using TCGA data. The difference was statistically significant with a logrank p-value less than 0.05. As a result, LINC00511 has an effect on the survival rate of patients with adrenocortical carcinoma (ACC), breast invasive carcinoma (BRCA), kidney renal clear cell carcinoma (KIRC), acute myeloid leukemia (LAML), liver hepatocellular carcinoma (LIHC), Mesothelioma (MESO), pheochromocytoma and paraganglioma (PCPG) and sarcoma (SARC) (Figure 3). While in patients with LAML, overexpression of this lncRNA is associated with better clinical outcome, in other types of cancers, its upregulation is associated with lower survival.

Discussion
LINC00511 is a lincRNA being over-expressed in a variety of human tumors and cancer cell lines. Except for a single study in osteosarcoma (Qiao et al., 2020), other studies in this type of cancer and other cancers have reported upregulation of LINC00511 in tumoral tissues compared with their nontumoral counterparts. Dysregulation of LINC00511 affects cancer pathogenesis through increasing cell proliferation and inhibiting cell apoptosis. It can also increase activity of several cancer-promoting signaling pathways.
A previous meta-analysis has reported association between over-expression of LINC00511 and poor prognosis in different cancers in terms of overall, progression-free or relapse-free survival times (Agbana et al., 2020). Moreover, upregulation of this lncRNA has been associated with larger tumor size, recurrent disorder and metastasis to lymph nodes or distant organs (Agbana et al., 2020).
LINC00511 can induce stemness in cancers and facilitate tumor progression and metastasis (Lu et al., 2018). Therefore, LINC00511modifying modalities can be used as possible strategies for defeating cancer metastasis.
The prognostic role of over-expression of LINC00511 in different cancers has been evaluated thoroughly by various research groups indicating its important effects on survival of affected individuals. Future studies should assess its expression in biofluids to provide a non-invasive route for cancer diagnosis and patients' follow-up.

Author contributions
MT designed and supervised the study. SG-F wrote the draft and revised it. AS, BH, and SA collected the data and designed the figures and tables. All the authors read the submitted version and approved it.

Funding
This study was Financially supported by Shahid Beheshti University of Medical Sciences.