Advances of lncRNA MAFG-AS1 in cancer

LI Bing, TIAN Yuan-yuan, SUN Xiao-ning, WANG Jiao

1. Department of Gastroenterology, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, China

2. Hainan Medical University, Haikou 571199, China

3. Department of Infectious, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, China

Keywords:

ABSTRACT In recent years, with the development of medical technology, the detection rate of cancer is getting higher and higher, and the population of patients is getting younger.Many studies have begun to study the early diagnosis, prognostic monitoring markers and pathogenesis of cancer.In recent years, with the development of bioinformatics technology, lncRNA have gradually attracted the attention of researchers.More and more studies have shown that lncRNA are responsible for various biological functions in the process of cancer progression.lncRNA MAFG-AS1 has been shown to be associated with multiple cancers, function as an oncogene,and is significantly associated with poor clinical features and prognosis.This article reviews the research progress of lncRNA MAFG-AS1 in cancer, hoping to provide some help for the future clinical diagnosis and treatment of cancer.

Current epidemiological statistics show that the incidence of cancer is increasing, which has caused serious health burden to human beings.It is necessary to strengthen the existing prevention,screening, diagnosis and disease management strategies of cancer[1].Oncogenesis is associated with the activation of proto-oncogenes and inactivation of tumor suppressor genes.In the final analysis,the occurrence of cancer is inseparable from genomic changes, and efforts have been made to discover the genes that drive or inhibit cancer progression[2-5].In recent years, the field of non-coding RNAs has made great progress due to the emergence of highthroughput experimental techniques[6].Although these types of RNA transcripts are not translated into proteins, they play a crucial role in regulating gene expression[7].LncRNAs are a class of noncoding RNA molecules with a length of more than 200 bases,which are mostly expressed in the nucleus and cytoplasm.They are mainly involved in a variety of biological processes such as chromatin modification, genome modification, nuclear transport,transcriptional interference, and transcriptional activation.Although lncRNA does not encode any functional protein, it can participate in the occurrence and development of diseases by acting as a decoy molecule, a guide molecule, a signal molecule and a scaffold molecule to interact with DNA, RNA and protein respectively[8].Recent studies have confirmed that lncRNAs may act as oncogenes or tumor suppressors depending on the cellular background and cancer type[9].Moreover, their dysregulation accelerates the proliferation, migration and invasion of cancer cells by interacting with multiple signaling pathways[10].Basic leucine zipper family transcription factor V-Maf avian myofascial fibrosarcoma oncogene homolog G(MAFG) -antisense RNA 1(AS1) is a newly discovered lncRNA in recent years.Studies have reported that lncRNA MAFGAS1 is up-regulated in various cancer tissues such as liver cancer and breast cancer, and can promote tumor cell proliferation and invasion[11, 12].

1.Relationship between lncRNA MAFG-AS1 and cancer

1.1 LncRNA MAFG-AS1 in gastrointestinal cancer

1.1.1 Esophageal cancer

Qu and Qian etal.found that LncRNA MAFG-AS1 accelerated cell migration, invasion and aerobic glycolysis of esophageal squamous cell carcinoma cells through miR-765/PDX1 Axis.Compared with adjacent non-tumor tissue and normal esophageal cells, MAFG-AS1 in esophageal squamous cell carcinoma (ESCC)Up-regulated in tissue samples and cell lines.Higher expression of MAFG-AS1 indicates poor survival.MAFG-AS1 acts as a ceRNA to raise LASP1 levels by sponging miR143 and plays a carcinogenic role in ESCC.Meanwhile, MAFG-AS1 competitively adsorbs miR-765, while miR-765 negatively regulates the expression of PDX1.miR-765 and PDX1 are involved in the promotion of MAFG-AS1 on ESCC cell migration, invasion and aerobic glycolysis[13, 14].

1.1.2 Gastric cancer

It was found that LncRNA MAFG-AS1 up-regulates Polo-Like Kinase-1 through sponge miR-505 to promote the proliferation of gastric adenocarcinoma cells.MAFG-AS1 interacts with miR-505, but the overexpression of MAFG-AS1 and miR-505 has no significant effect on the expression of each other.In addition,MAFG-AS1 increased the expression of PLK1, a miR-505 target.Overexpression of MAFG-AS1 and PLK1 increased the proliferation rate of GC cells[15].We found that compared with normal gastric mucosa and normal gastric epithelial cell lines, MAFG-AS1 expression was significantly increased in gastric cancer tissues and cell lines, and high expression of MAFG-AS1 was associated with diffuse, advanced clinical stage, extensive and deep gastric cancer patients with more invasive, lymph node metastasis, and distant metastasis.In addition, high expression of MAFG-AS1 is an independent adverse prognostic factor for overall survival of patients with gastric cancer.Loss of function studies have shown that in vitro knockout of MAFG-AS1 expression can inhibit the proliferation,migration and invasion of gastric cancer cells.In conclusion, MAFGAS1 may be a valuable prognostic biomarker and a new potential target for gastric cancer[16].

1.1.3 Colorectal cancer

The carcinogenic function of LncRNA MAFG-AS1 was first observed in colorectal cancer (CRC).Studies have shown that compared with normal cells and tissues, MAFG-AS1 is a key factor in the pathogenesis and metabolism of CRC cells, and its expression is up-regulated in tumor tissues.The role of MAFGAS1 in promoting cell proliferation, cell cycle progression, invasion and glycolysis as well as inhibiting cell apoptosis has been well demonstrated[17].Later, studies in different cohorts confirmed that MAFG-AS1 expression was increased in colorectal cancer cells[17,19].In addition, the higher the expression of this lncRNA, the higher the TNM stage and the depth of invasion[17].Kaplan-Meier test of 172 patients with colorectal cancer showed that patients with higher MAFG-AS1 had shorter overall survival and disease-free survival[17].In addition, MAFG-AS1 promoted the proliferation, migration and invasion of colorectal cancer cells by inhibiting the expression of miRNA miR-147b[17] and miR-149-3p[20].Downregulation of these miRNAs lead to upregulation of NDUFA4 and HOB8, promoting cellular glycolysis and tumorigenicity in vivo.

1.1.4 Hepatocellular carcinoma

As a common digestive tract tumor, LncRNA MAFG-AS1 also plays a certain role in promoting the carcinogenesis of liver cancer.Existing studies have demonstrated that lncRNA MAFG-AS1 expression is increased in HCC tissues and cell lines.After knocking down lncRNA MAFG-AS1, Cell Counting Kit-8 and Transwell assay showed that the proliferation, migration and invasion of HCC cell lines were significantly inhibited.A negative regulatory association between lncRNA MAFG-AS1 and miR-6852 was also demonstrated.Inhibition of miR-6852 increased the proliferation,migration and invasion of HCC cell lines.LncRNA MAFG-AS1 promotes HCC development by inhibiting the function of miR-6852 [11].In addition, LncRNA MAFG-AS1 regulates the formation of hepatocellular carcinoma through other mechanisms, that is,MAFG-AS1 promotes the progression of HCC by targeting miR-3196/OTX1 axis.MiR-3196 is sponged by MAFG-AS1, and OTX1 is the downstream target of miR-3196 in HCC.In addition, OTX1 expression was negatively correlated with miR-3196, but positively correlated with MAFG-AS1 in HCC tissues.Overexpression of OTX1 can eliminate the inhibitory effect of MAFG-AS1 inhibition on HCC cell proliferation, migration, invasion and tumor angiogenesis[21].lncRNA MAFG-AS1 also enhances drug resistance in HCC by regulating Mir-3196-mediated STRN4[22].

1.2 LncRNA MAFG-AS1 in urogenital canal

1.2.1 Bladder cancer

Bladder cancer is the most common malignant tumor of urinary system.Recent studies have focused on the diagnostic and prognostic value of lncRNA in bladder cancer, indicating that lncRNA is a new target and biomarker in the pathogenesis of bladder cancer[23].Multiple studies on bladder cancer tissue samples showed that MAFG-AS1 was positively correlated with lymph node metastasis,histological grade, clinical stage, and tumor size (P ＜ 0.05).These studies also confirmed the promoting effect of MAFG-AS1 on the proliferation, invasion, metastasis and EMT of bladder cancer cells [23, 24].At the molecular level, MAFG-AS1 directly interacts with miR-143-3p and an RNA-binding protein called Hu Antigen R (HuR) to facilitate the above process.More specifically, MAFGAS1 prevents proteasome degradation of HuR by recruiting USP5 as a deubiquitase and promotes RNA stability of polypyrimidine bunchbinding protein 1 (PTBP1)[24].In addition, MAFG-AS1 upregates two cyclooxygenase-2 (COX-2) and SERPINE1, which are involved in bladder cancer progression along with PTBP1,through its sponging action on miR-143-3p[25].Other studies have shown that MAFG-AS1 has a carcinogenic effect in bladder cancer by regulating the miR-125b-5p/SphK1 axis.The specific mechanism is that SphK1 is the downstream target of miR-125b-5p and is negatively correlated with miR-125b-5p, while positively correlated with MAFG-AS1 in the whole bladder cancer tissue.The overexpression of MAFG-AS1 upregulated the expression of SphK1 in bladder cancer cells and weakened the inhibitory effect of miR-125b-5p on SphK1 expression.The overexpression of miR-125b-5p inhibited the proliferation, migration and invasion of BC cells, while the overexpression of SphK1 mitigated its effect[26].In addition, MAFG-AS1 also plays a role in the resistance of bladder cancer.The binding of MAFG-AS1 to iron-mate poly (rc) binding protein 2 (PCBP2) promotes the recruitment of MAFG-AS1 to the deubiquitination enzyme ubiquitin carboxy-terminal hydrolase isoenzyme L5 (UCHL5), thus stabilizing the PCBP2 protein itself.PCBP2 was then shown to interact with ferric transporter 1 (FPN1),an iron-exporting protein that inhibits iron death.MAFG-AS1 /MAFG positive feedback loop promotes cisplatin resistance in bladder cancer by antagonizing iron death[27].

1.2.2 Prostate cancer

Prostate cancer has a good prognosis if it is diagnosed and treated early.Studies have shown that MAFG-AS1 can promote the progression of prostate cancer and is a prognostic biomarker.In this study, using TCGA data from 495 patients with prostate cancer and tissue analysis from 2 patients with metastatic prostate cancer,including PC-3 and DU145 cell lines, conclusions were drawn:The expression of MAFG-AS1 is significantly higher than that of normal adjacent tissues, and is also related to the TNM staging of tumors.Knockdown of MAFG-AS1 can inhibit the proliferation,migration and invasion of prostate cancer cells[28].The main relevant mechanism is that MAFG-AS1 in prostate cancer is involved in 5-methylcytosine (m5C) RNA modification, which affects gene expression by regulating RNA translation, output, stability and ribosome assembly, leading to proliferation and invasion of prostate cancer cells[29].

The carcinogenic effect of lncRNA MAFG-AS1 on urogenital tract tumors has also been confirmed to some extent.They are similar to digestive tract tumors in that they act through specific cellular pathways.In bladder cancer, existing studies have shown that MAFG-AS1 promotes the occurrence of bladder cancer tumors by regulating the miR-125b-5p/SphK1 axis and the miR-143-3p/SERPINE1 axis, but the specific cell pathway is dominant, or the two effects are evenly balanced, which has not been confirmed by Chinese studies.This issue still needs further discussion.In terms of drug resistance in bladder cancer, current studies have shown that the MAfG-AS1 /MAFG positive feedback loop promotes cisplatin resistance in bladder cancer through antagonistic iron death.Further studies can be conducted on whether the positive feedback loop of MAFG-AS1 /MAFG can improve the drug resistance of tumors to cisplatin.

1.3 Breast cancer

Breast cancer is a more common malignant tumor in women,and its incidence is increasing in recent years.Regarding the role of lncRNA MAFG-AS1 in breast cancer, a considerable number of studies have confirmed that compared with normal breast tissue, lncRNA MAFG-AS1 expression level in breast cancer is up-regulated, and its carcinogenic effect is beyond doubt[30, 31].However, as far as current studies are concerned, lncRNA MAFGAS1 is involved in numerous signaling pathways related to the regulation of breast cancer, and MAFG-AS1 seems to play an oncogene role in breast cancer by regulating miR-339-5p/MMP15[12].It can also affect tumorigenesis of breast cancer cells through miR-574-5p/SOD2 axis[31], and studies have shown that MAFGAS1 promotes proliferation and metastasis of breast cancer by regulating STC2 pathway[30], and influences autophagy and progression of breast cancer through in vitro interaction with miR-3612 and FKBP4.MAFG-AS1 and FKBP4 are highly expressed in breast cancer tissues.MAFG-AS1 can be used as an oncogene in breast cancer to activate cell proliferation, inhibit apoptosis and autophagy.At the same time, MAFG-AS1 can sponge miR-3612 to improve the expression of FKBP4.In addition, FKBP4 can activate cell proliferation and inhibit cell apoptosis and autophagy, thus alleviating the inhibitory effect of miR-3612 on breast cancer cells[32].In terms of drug resistance in breast cancer, crosstalk between ER signaling pathway and cell cycle conducted by MAFG-AS1 and CDK2 can promote tamoxifen resistance.Estrogen-responsive lncRNA MAFG-AS1 up-regulates CDK2 via spongy miR-339-5p,thereby promoting the proliferation of ER+ breast cancer.Crossdialogue between ER signaling pathways and cell cycles suggests that lncRNA MAFG-AS1 is a potential biomarker and therapeutic target for ER+ breast cancer[33].

1.4 Lung cancer

In terms of lung cancer, current studies have shown that lncRNA MAFG-AS1 has a regulatory role in non-small cell lung cancer and lung adenocarcinoma[34, 35].In lung adenocarcinoma, LncRNA MAFG-AS1 promotes the proliferation, migration and invasion of lung adenocarcinoma cells by regulating the miR-744-5p/MAFG axis, targeting miR-3196 and regulating SOX12 expression[34, 36].The specific mechanism is increased expression of MAFG-AS1 in tissues, which is associated with poor prognosis.MAFG-AS1 saved the inhibition of SOX12, the target of miR-3196, by acting as an endogenous sponge directly targeting miR-3196[36].In addition,Mafg-AS1 as a molecular sponge of miR-744-5p, upregulates the nearby gene MAF bZIP transcription factor also G (MAFG) in lung adenocarcinoma cells.Functionally, overexpression of MAFG attenuates the cellular processes mediated by Mafg-AS1 knockdown,thus achieving the role of cancer promotion[34].In non-small cell carcinoma of lung (NSCLC), LncRNA MAFG-AS1 promotes migration and invasion of NSCLC cells through miR-339-5p in spongy MMP15.The overexpression of MAFG-AS1 significantly decreased the level of miR-339-5p in NSCLC cells.Matrix metalloproteinase 15 (MMP15) was identified as the target of miR-339-5p, and MMP15 level was negatively regulated by miR-339-5p.Under the positive regulation of MAFG-AS1, the up-regulation of miR-339-5p neutralized the promoting effect of MAFG-AS1 on the migration, invasion and EMT of NSCLC cells.Xenograft models showed that MAFG-AS1 promoted the metastasis of NSCLC cells in vivo[35].

In breast cancer and lung cancer, lncRNA MAFG-AS1 has also been confirmed to be associated with the occurrence, proliferation and invasion of tumors, and the higher level of expression indicates a poor prognosis, suggesting that lncrNA MAFG-AS1 may be used as a marker for prognostic monitoring.Currently, relevant studies have confirmed that lncRNA MAFG-AS1 plays a regulatory role in breast cancer, and indicated that lncRNA MAFG-AS1 can regulate more cellular pathways, and also revealed the mechanism of tamoxifen resistance of MAFG-AS1 on estrogen-antibody positive breast cancer.Whether MAFG-AS1 is related to other drug resistance is still lacking.In lung cancer, MAFG-AS1 has been mainly confirmed to play a certain regulatory role in adenocarcinoma and non-small cell carcinoma, while studies on squamous cell carcinoma have not been reported so far.

2.Clinical significances of MAFG-AS1 in cancers

As concluded in the above studies, lncRNA MAFG-AS1 is involved in the carcinogenic process of a variety of cancers, and is related to the proliferation, migration and invasion of cancer cells to some extent.MAFG-AS1 can be used as a diagnostic and prognostic biomarker for a variety of cancers.MAFG-AS1 is directly related to clinical stage, greater invasion depth, lymph node metastasis, and the presence of distant metastasis.High expression of MAFG-AS1 often indicates poor prognosis, short overall survival and diseasefree survival.Studies have shown that lncRNA MAFG-AS1 can distinguish normal liver tissue from tumor tissue by subject operating characteristic curve under certain threshold setting[18].It can be concluded that lncRNA MAFG-AS1 can be used as a marker for cancer diagnosis and disease diagnosis under reasonable threshold.In the studies on drug resistance, the current studies involving lncRNA MAFG-AS1 on drug resistance to tumors have only been reflected in liver cancer, bladder cancer and breast cancer, and there is a clear mechanism pathway of drug resistance.In future studies,related blockers can be developed to block drug resistance pathway,so as to improve the sensitivity of drug therapy and improve the treatment quality of patients.rates.From the above studies, we can conclude that lncRNA MAFGAS1 is related to digestive tract tumors, genitourinary tract tumors,breast cancer, lung cancer and other tumors, and it is related to tumor size, depth of invasion and clinical stage to a certain extent.High level of expression often indicates poor prognosis, short survival and other problems.Therefore, lncRNA MAFG-AS1 can play a certain role in the early diagnosis and prognostic monitoring of the disease.However, the fact that lncRNA MAFG-AS1 has been shown to be associated with a variety of diseases indicates that its specificity when used as an exact diagnostic marker of diseases is doubtful.Therefore, further studies are needed on the sensitivity and specificity of lncRNA MAFG-AS1 in the disease spectrum, and it is better to determine a reasonable threshold.Thus, lncRNA MAFGAS1 can be used as a molecular marker for diagnosis and prognosis monitoring in clinic.Second, lncRNA MAFG-AS1 is involved in the mechanism of drug resistance in tumors.At present, there are few studies on lncRNA MAFG-AS1 drug resistance at home and abroad, which only exists in liver cancer, bladder cancer and breast cancer, and few related drugs are involved.Future studies in this aspect should be expanded.Finally, from the perspective of lncRNA MAFG-AS1 detection, it is relatively simple and fast to extract lncRNA MAFG-AS1 from blood samples if it is used as a marker for early diagnosis and prognostic monitoring.However, most of the above studies extracted lncRNA MAFG-AS1 from tissue samples.In addition, by comparing the expression levels in normal tissues and tumor tissues of tumor patients, it can be concluded that it is highly expressed in tumor tissues, so as to be pre-set as a marker for disease diagnosis.However, whether the results from tissue samples can be applied to blood samples and used to distinguish patients from normal people will need to be confirmed by blood samples.Studying the role of lncRNA MAFG-AS1 in the pathogenesis of cancer and exploring the mechanism of drug resistance can further improve the early diagnosis rate of cancer patients and reduce drug resistance to treatment, improve the quality of treatment, and expect to have better clinical benefits in the future.

Authors’ contribution

Bing Li: Read literature and write papers; Yuanyuan Tian:Collecting literature; Jiao Wang : Collecting literature; Xiaoning Sun: Thesis guidance;

All authors declare no conflict of interest

3.Summary and prospect

Cancer is a disease related to environmental, immune, genetic,microbial and other factors.In essence, it is a disease caused by the mutation of proto-oncogene and the activation of tumor suppressor gene under certain circumstances, which leads to the continuous proliferation of tumor cells that should be apoptotic.With the pollution of environment and water quality, the abuse of food additives in recent years, the prevalence of cancer is increasing.Advances in medical technology have also increased cancer detection