Open access peer-reviewed chapter

Interactions of lncRNAs and miRNAs in Digestive System Tumors

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Hussein Al-Dahmoshi, Noor Al-Khafaji, Moaed E. Al-Gazally, Maha F. Smaism, Zena Abdul Ameer Mahdi and Suhad Y. Abed

Submitted: June 17th, 2022 Reviewed: August 25th, 2022 Published: October 7th, 2022

DOI: 10.5772/intechopen.107374

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Abstract

Noncoding RNA (ncRNA) includes short (miRNA) and long (lncRNA) that have important regulatory role in different biological processes. One of the important issue in which ncRNA involved is tumor induction and suppression. miRNA and lncRNA were vital players in many tumors including digestive system tumors. This study includes studying the role of 140 hsa-miR including miR-1 to miR-140 and their sponger lncRNA in esophageal and stomach cancers by 249 studies. The review revealed that each miR may play as oncogene only or tumor suppressor via upregulation and downregulation regulatory proteins in cell cycles and activation of physiological cascades. Some of miR have dual role in same type of tumor as oncogene and suppressive miR. Same thing is for lncRNA tacting as oncogenic via sponging some of miR when overexpressed to upregulate oncogenic protein or acting as suppression lncRNA when overexpressed to downregulate some oncogenic proteins activated by miR. The current review concludes the vital role of ncRNA (both miRNA and lncRNA) in some digestive system tumors as oncogene-promoting cancer viability, invasiveness, proliferation, and metastasis or as tumor suppressor inhibiting tumorigenicity or inducing apoptosis.

Keywords

  • miRNA
  • lncRNA
  • sponge
  • oncogene
  • tumor suppressor
  • esophageal tumors
  • gastric cancers

1. Introduction

Ribonucleic acids (RNAs) are important nucleic acids for cell life and are classified as coding and non-coding RNA (ncRNAs). MicroRNAs (miRNAs) are a class of short noncoding RNAs (ncRNAs) (22 nts) that play important roles in posttranscriptional gene regulation. The majority of miRNAs are transcribed from DNA sequences into primary miRNAs and processed into precursor miRNAs, and finally mature miRNAs [1]. Long noncoding RNAs (lncRNAs) (more than 200 nts) may regulate cell proliferation, apoptosis, migration, invasion, and maintenance of stemness during cancer development [2, 3]. miRNA has a role in many tumors and upregulation/downregulation status of them may influence tumorigenesis, proliferation, metastasis, and chemoresistance [4, 5]. miRNAs implicated as oncogene of repressors for sets of cancers of liver: focal nodular hyperplasia (FNH) [6], hepatocellular adenoma (HCA) [7], hepatocellular carcinoma (HCC) [8], and cholangiocarcinomas (CCA) [9]. miRNAs were also implicated in pancreatic cancers: pancreatic endocrine tumors (PET) [10], pancreatic ductal adenocarcinoma (PDAC), and pancreatic acinar cell carcinoma (PACC) [11]. Esophageal squamous-cell carcinoma (ESCC) [12], and esophageal adenocarcinoma (EAC) [13], stomach adenocarcinoma (STAD) [14], colon adenocarcinoma (COAD) [15] were also influenced by miRNAs. The current review focused on 140 types of miR (miR-1 to miR-140) as oncogenic or tumor suppressor miR in different digestive system tumors.

1.1 Esophageal cancers

Esophageal cancer is a disease in which malignant (cancer) cells form in the tissues of the esophagus. It is characterized by its high mortality rate and poor prognosis. This disease is the sixth cause of cancer-related deaths and the eighth most common cancer worldwide with a 5-year survival rate of less than 25% [15]. Esophageal cancer occurs as either squamous cell carcinomas (ESCC) or adenocarcinoma (EAC). ncRNA including miRNA and lncRNA has a vital role in esophageal cancers either as oncogenic or as tumor suppressor [16, 17].

1.1.1 lncRNA/miR interaction in esophageal squamous cell carcinoma (ESCC)

Esophageal squamous cell carcinoma (ESCC) is a cancer that forms in the thin, flat cells lining the inside of the esophagus. It accounts for about 90% of esophageal cancers. miRNA can play a vital role in cancer regulation and may be an oncogene or tumor suppressor gene when overexpressed. In esophageal squamous cell carcinoma (ESCC), miR-1, −22, −26, −27, −29, −30, −33, −34, −98, −99, −100, −101, −107, −122, −124, −125, −127, −128, −129, −133, −134, −136, −137, −138, −139, and − 140 were downregulated in ESCC tissues compared with normal one acting as tumor suppressor and targeting different genes [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43]. In contrast, the expression of miR-7, −9, −10, −16, −17, −18, −19, −20, −21, −23, −24, −25, −28, −31, −32, −92, −93, −96, −103, −105, −106, −126, −130-, and miR-135 was upregulated in ESCC acting as oncogene [44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66], as shown in Table 1.

miRNAExpression in ESCCRole in ESCCTarget geneRef.
miR-1DownregulatedTumor-suppressorNOTCH2, LASP1[18]
miR-22DownregulatedTumor-suppressorPTEN, C-MYC[19]
miR-26DownregulatedTumor-suppressorMYCBP[20]
miR-27DownregulatedTumor-suppressorFBXW7[21]
miR-29DownregulatedTumor-suppressorFBXO31[22]
miR-30DownregulatedTumor-suppressorITGA5, PDGFRB[23]
miR-33DownregulatedTumor-suppressorZEB1[24]
miR-34DownregulatedTumor-suppressorc-MET, FOXM1[25]
miR-98DownregulatedTumor-suppressorEZH2[26]
miR-99DownregulatedTumor-suppressorCCND1, CCNA2[27]
miR-100DownregulatedTumor-suppressorCXCR7[28]
miR-101DownregulatedTumor-suppressorCOX-2[29]
miR-107DownregulatedTumor-suppressorCDC42[30]
miR-122DownregulatedTumor-suppressorKIF22[31]
miR-124DownregulatedTumor-suppressorBCAT1[32]
miR-125DownregulatedTumor-suppressorp38-MAPK[33]
miR-127DownregulatedTumor-suppressorFMNL3[34]
miR-128DownregulatedTumor-suppressorZEB1[35]
miR-129DownregulatedTumor-suppressorCTBP2[36]
miR-133DownregulatedTumor-suppressorCOL1A1[37]
miR-134DownregulatedTumor-suppressorFOXM1[38]
miR-136DownregulatedTumor-suppressorMUC1[39]
miR-137DownregulatedTumor-suppressorEZH2, PXN[40]
miR-138DownregulatedTumor-suppressorNF-κB[41]
miR-139DownregulatedTumor-suppressorNR5A2[42]
miR-140DownregulatedTumor-suppressorZEB1[43]
miR-7DownregulatedTumor-suppressorHOXB13[44]
miR-9OverexpressedOncogeneE-cadherin, FOXO1[45]
miR-10OverexpressedOncogeneFOXO3, KLF4[46]
miR-16OverexpressedOncogeneRECK, SOX6[47]
miR-17OverexpressedOncogeneRBL2[48]
miR-18OverexpressedOncogeneKRAS[49]
miR-19OverexpressedOncogeneCDC42, RAC1[50]
miR-20OverexpressedOncogeneRB1, TP53INP1[51]
miR-21OverexpressedOncogeneTPM1, PTEN[52]
miR-23OverexpressedOncogeneEBF3[53]
miR-24OverexpressedOncogeneFBXW7[54]
miR-25OverexpressedOncogenePTEN, ZNF512B[55]
miR-28OverexpressedOncogeneARF6[56]
miR-31OverexpressedOncogeneLATS2[57]
miR-32OverexpressedOncogeneCXXC5[58]
miR-92OverexpressedOncogenePTEN[59]
miR-93OverexpressedOncogeneTGFβR2[60]
miR-96OverexpressedOncogene[61]
miR-103OverexpressedOncogeneCDH11, NR3C1[62]
miR-105OverexpressedOncogeneSPARCL1, FAK[63]
miR-106OverexpressedOncogenePTEN[64]
miR-126OverexpressedOncogeneSTAT3[65]
miR-135OverexpressedOncogeneRERG[66]

Table 1.

Oncogenic/tumor-suppressor miR among ESCC.

Actually, lncRNA may have oncogenic activity acting as molecular sponge to inhibit activity of tumor suppressor miR. lncRNA opposite in action with tumor suppressor miR will act as oncogenic lncRNA, as shown in Table 2. HOX transcript antisense RNA (HOTAIR) expression increased in ESCC and inhibit the activity of miR-1. HOTAIR can be used as diagnostic marker of ESCC. miR-1 exert its suppressive action on ESCC via gene suppression of hepatocyte-growth factor (CCND1, CDK4, and MET). HOTAIR-mediated sponging of miR-1 leads to upregulation of those growth factors leading to ESCC proliferation and propagation [67]. Zinc finger E-box binding homeobox 1 (ZEB1) is transcriptional factor responsible for metastasis in ESCC, which is dysregulated by miR-33 to improve the outcome of ESCC. Differentiation antagonizing nonprotein coding RNA (DANCR) is lncRNA, which downregulates miR-33 and upregulates ZEB1 and so participates in worseness of ESCC [68]. Another lncRNA called MIR31HG acts on miR-34 leading to upregulation of c-Met promoting ESCC [69]. SNHG16 is also lncRNA of miR-98 that directly binds to enhancer of zeste homolog 2 (EZH2) and promotes ESCC propagation [70]. ANRIL is lncRNA of miR-99, which also promotes ESCC proliferation via downregulation of miR-99 [71]. MALAT1 lncRNA may decrease the expression of miR-101 and promote ESCC proliferation and metastasis via upregulation of [72]. Additionally, FAM201A lncRNA acts as a sponge for miR-101 and upregulates mTOR [73]. miR-107 targeting Ras-related protein Rab-10 (Rab10) and decreasing their expression and preventing ESCC propagation. LINC00152 is sponge lncRNA of miR-107, which promotes ESCC via overexpression of Rab10 upon miR-107 sponging [74]. Additionally LINC01296 sponge miR-122 and increasing mTOR expression [75]. ZFAS1 lncRNA was found to promote the proliferation, migration, and invasion of ESCC by upregulating STAT3 and downregulating miR-124 [76]. HOTAIR could increase the expression of hexokinase 2 (HK2) in ESCC through sponging of miR-125 [77]. Nuclear paraspeckle assembly transcript 1 (NEAT1) is lncRNA that sponge miR-129 and upregulates their target, CTBP2, promoting ESCC viability and invasion [36]. H19 lncRNA inhibits the effect of miR-138 and promotes EZH2 thereby promoting ESCC [78]. Breast cancer antiestrogen resistance 4 (BCAR4) lncRNA act to sponged miR-139-3p, leading to upregulation of ELAVL1 and promoting tumorigenesis of ESCC [79]. SNHG16 lncRNA squeegee miR-140 and upregulates their target, ZEB1, thereby promoting ESCC [43]. lncRNA LincIN has been reported to be overexpressed and to be involved in the metastasis of breast cancer. LincIN has the potential role in ESCC invasion and metastasis via upregulation of HOXB13 and downregulation of miR-7 + enhancement of binding between NF90 on primary miR-7. It seem that no sponge lncRNA were documented for miR-22, −26, −27, −29, −30, −100, −127, −128, −133, −134, −136, and miR-137 in ESCC yet.

lncRNAExpression of lncRNA in ESCCTarget miRTarget geneRef.
HOTAIROverexpressedmiR-1CCND1, CDK4, and MET[67]
DANCROverexpressedmiR-33ZEB1[68]
MIR31HGOverexpressedmiR-34c-Met[69]
SNHG16OverexpressedmiR-98EZH2[70]
ANRILOverexpressedmiR-99[71]
MALAT1OverexpressedmiR-101[72]
FAM201AOverexpressedmiR-101mTOR[73]
LINC00152OverexpressedmiR-107Rab10[74]
LINC01296OverexpressedmiR-122mTOR[75]
ZFAS1OverexpressedmiR-124STAT3[76]
HOTAIROverexpressedmiR-125HK2[77]
NEAT1OverexpressedmiR-129CTBP2[36]
H19OverexpressedmiR-138EZH2[78]
BCAR4OverexpressedmiR-139ELAVL1[79]
SNHG16OverexpressedmiR-140ZEB1[43]
LincINOverexpressedmiR-7HOXB13[80]
MEG3DownregulatedmiR-9E-cadherin, FOXO1[81]
FAM83H-AS1OverexpressedmiR-10[82]
PART1DownregulatedmiR-18SOX6[83]
GAS5DownregulatedmiR-21RECK[84]
AC012073.1DownregulatedmiR-93[85]

Table 2.

Oncogenic/tumor suppressor lncRNA among ESCC.

lncRNA can act as tumor suppressor counteracting the effect of oncogenic miR. Maternally expressed gene 3 (MEG3) is tumor suppressor lncRNA of miR-9. MEG3 decreased expression was seen in ESCC. Expression level of MEG3 was significantly increased in cancer cells after being treated with the DNA methyltransferase inhibitor 5-Aza-dC, leading to decreased miR-9 and increased E-cadherin and FOXO1 expression [81]. miR-10 can be sponged by lncRNA FAM83H-AS1 in ESCC [82]. Prostate androgen-regulated transcript 1 (PART1) lncRNA was downregulated in ESCC and, when overexpressed, will sponge oncogenic miR-18 leading to upregulation of SOX6 thereby inhibiting ESCC proliferation and metastasis [83]. Growth arrest-specific 5 (GAS5) lncRNA is seen to be elevated in radiation-sensitive ESCC tissues, leading to dysregulation of miR-21 and increasing the level of its target, RECK [84]. lncRNA called AC012073.1 is seen to bind competitively to miR-93 in ESCC [85] as shown in Table 2.

1.1.2 lncRNA/miR interaction in esophageal adenocarcinoma (EAC)

Esophageal adenocarcinoma (EAC) is a malignancy classically seen in the distal esophagus. The incidence of EAC is seven times more common in men than in women [86]. lncRNA and miRNA can either be oncogenic promoting tumor proliferation, invasion, and metastasis or acting as a tumor suppressor via targeting specific protein and signaling pathways. It seems few studies were conducted on miR role in tumorigenesis or anti-tumor in EAC, but many studies highlighted the pivotal role of lncRNA. lncRNA called miR205HG was found to have tumor suppressory effect on EAC when overexpressed via downregulation of the Hedgehog (Hh) signaling pathway [87]. lncRNA HOTAIR expression was upregulated in EAC tumor acting as oncogene via regulating NTRK2, NP1, CHRDL1, NTRK2, HOXC8, and IL11. Inversely lncRNA CYP1B1-AS1 was downregulated in EAC acting as tumor supressor [88]. Two lncRNA called AFAP1-AS1 and HNF1A-AS1 were shown to be overexpressed in EAC acting as oncogene [89, 90]. PVT1 lncRNA was also documented as oncogene via upregulation of YAP1 in EAC tissues [91]. Also, MIR22HG lncRNA has same effect on PVT1 (oncogenic) via activation of STAT3/c-Myc/p-FAK pathway. Tumor suppressor lncRNA like BDNF-AS and ADAMTS9- AS2 can exert their suppressive activity via sponging miR-214 and CDH3, respectively [92, 93]. Another oncogenic lncRNA, LINC00662, utilizes its effect via activating Wnt/β-catenin signaling (Table 3) [94].

lncRNAExpression of lncRNA in EACTarget miRTarget geneRef.
miR205HGDownregulatedNAHedgehog[87]
HOTAIROverexpressedNANTRK2, NP1, CHRDL1, NTRK2, HOXC8 and IL11[88]
CYP1B1-AS1DownregulatedNANA[88]
AFAP1-AS1OverexpressedNANA[89]
HNF1A-AS1OverexpressedNAH19[90]
PVT1OverexpressedNALATS1, YAP1[91]
MIR22HGOverexpressedNASTAT3[92]
BDNF-ASDownregulatedmiR-214JAG1[92]
ADAMTS9- AS2DownregulatedNACDH3[93]
LINC00662OverexpressedNAWnt/β-catenin[94]

Table 3.

Oncogenic/tumor suppressor lncRNA among EAC.

1.2 Stomach cancers

Gastric or stomach cancers were also regulated by miR/lncRNA interactions. miR-1 directly targets the MET gene and downregulates its expression acting as tumor suppressor [95]. MET is an oncogene and its activation results from the binding of hepatocyte growth factor (HGF), leading to tumor growth, metastasis, migration, and drug resistance [96]. Targeting MET by miR-1 will deactivate it, and MET can restore its activity by oncogenic lncRNA called LINC00242 when sponging the miR-1 [97]. miR-7 also acting as a tumor suppressor in gastric cancer may be via degradation of EGFR mRNA, and thus, the oncogenic lncRNA UCA1 can sponge miR-7, leading to enhancing the expression of EGFR and promoting cell metastasis and migration [98]. miR-9 is implicated as oncogenic via downregulation of CDX2 and promotes gastric cancer cell proliferation [99] and may act as tumor suppressor that can be sponged by HULC lncRNA via upregulation of MYH9 [100]. miR-17, −18, −19, and − 20 were documented as oncogenic ncRNA among gastric cancer patients. Oncogenic miR-17 targeting PTEN and EGR2 to enhance proliferation and metastasis of stomach cancer, and this effect can be sponged by lncRNA HOTAIRM1 or LINC01939, which suppressed proliferation and migration of GC cell acting as tumor suppressor lncRNA [101, 102]. Inversely, lncRNA NEAT1 was overexpressed in gastric cancers and positively related with miR-17 via activation of GSK3β [103]. By targeting IRF2, miR-18 enhances proliferation and metastasis of gastric cancer [104]. Sponging of miR-19 by lncRNA CASC2 can increase the sensitivity to cisplatin and so it acts as tumor suppressor [105, 106].

<>Oncogenic miR-21 can promote gastric cancer cell viability and progression via downregulation of some tumor suppressor genes like PTEN, RECK, and PDCD4 [107]. Inhibiting miR-21 expression by lncRNA MEG3 can inhibit gastric cancer growth and metastasis [108]. miR-22 acts to suppress gastric cancer via upregulating MMP14, NET1, and Snail while lncRNA CTC-497E21.4 can squeegee miR-22 and promote proliferation and invasion [109]. miR-24 and miR-25 were upregulated in gastric cancer tissues and may promote the occurrence, development, infiltration, and metastasis of gastric cancer. As oncogenic miR-24 inhibits the CDKN1B and CHEK1 and miR-25 targeting FOXO3 [110, 111]. Tumor suppressor lncRNA GATA6-AS acts to inhibit gastric cancer progression by sponging miR-25 [112]. Targeting PTEN, miR-26 acts as oncogenic and upregulated in gastric cancer tissues promoting proliferation and invasion. Additionally, miR-26 can target EZH2 and can be suppressed by tumor suppressor lncRNA TET1–3 [113, 114]. miR-27 is additional oncogenic miR acting on HOXA10 [115]. By inhibiting the phosphorylation of AKT protein in gastric cancer cells, miR-28 acts as inhibiting progression and metastasis and can be sponged by LOC400043 [116, 117]. Low expression was seen in gastric cancer tissues for miR-29 highlighting their role as tumor suppressor targeting CCND2 and MMP2, and can be sponged by lncRNA MEG3 [118, 119]. As tumor suppressor, miR-30 is responsible for inhibiting gastric cancer and increasing sensitivity to anticancer drugs when upregulated [120], and lncRNA PVT1, HNF1A-AS1, and DLEU2 can sponge miR-30 and upregulating Snail protein, PI3K/AKT signaling pathway and ETS2, respectively, promoting gastric cancer cell proliferation and metastasis [121, 122, 123].

Conversely, it can be acting as oncogenic miR through P53/ROS-mediated regulation of the mitochondrial apoptotic pathway [124]. miR-31 acts as a vital tumor suppressor ncRNA by inhibiting E2F2s and RhoA expression, also upregulation of miR-31 targeting ITGA5 may suppress tumor cell invasion and metastasis by indirectly regulating PI3K/AKT signaling pathway in human SGC7901 GC cells [125, 126]. lncRNA MIR31HG can encourage gastric cancer cell proliferation and invasion via sponging miR-31 [127]. Another oncogenic miR is miR-32, which augments tumorigenesis of gastric cell cancer by targeting KLF4 and KLF2, and at the same time can be sponged by SNHG5 lncRNA [128]. Gastric cancer suppresivity of miR-33 and miR-34 by targeting CDK6, CCND1, and PIM1 via miR-33 and Bcl-2, Notch, and HMGA2 via miR-34 [129, 130].

Overexpression of miR-43 was seen in gastric cancer tissues that promotes proliferation and metastasis by targeting VEZT [131]. miR-92 suppresses proliferation of gastric cancer and induces apoptosis by targeting EP4, Notch1 [132], and by targeting SOX4 while sponging of miR-92 by lncRNA PITPNA-AS1 and MT1JP can promote gastric cancer migration via upregulation of SOX4 and FBXW7 respectively [133134]. Oncogenic miR-93 can promote tumorigenesis by downregulation of IFNAR1 or PTEN [135, 136], and gastric cancer suppressor lncRNA PTENP1, GPC5-AS1, and CA3-AS1 can achieve gastric cancer inhibition by sponging miR93 and upregulating PTEN, GPC5, and PTG3 respectively [136, 137, 138]. Dual effect of miR-95 targeting EMP1 as oncogene or tumor suppressor by targeting Slug [139140]. Oncogenic miR-96 can target ZDHHC5, KIF26A, and FOXO3 promoting gastric cancer cell viability [141, 142]. Downregulation of BCAT1 Treg and CCND2 by miR-98 as a tumor suppressor for gastric cancer [143, 144] and TTTY15 lncRNA can sponge miR-98 and upregulate CCND2 [145]. Tumor suppressor miR-100 can inhibit cell proliferation and induce apoptosis in human gastric cancer via downregulating many proteins, such as BMPR2 [146], ZBTB7A [147], and CXCR7 [148], or acting as oncogene via their antiapoptotic role by inhibiting ubiquitination-mediated p53 degradation [149] and upregulation of HS3ST2 [150]. Contrariwise, oncogenic lncRNA such as HAGLROS [151] and MIR100HG [152] were sponging miR-100 and promote tumorigenesis via activation of the mTORC1 signaling pathway [151], PI3K/AKT/mTOR pathway [153, 154].

Tumor suppressor miR-101 targeting: ANXA2 [155], ZEB1 [156], SOCS2 [157], PI3K/AKT/mTOR [158], EZH2 [159], and AMPK [160] and sponged by LINC01303 and lncRNA XIST by upregulating EZH2 [159, 161], lncRNA SPRY4-IT1 by upregulating AMPK [160], lncRNA SNHG6 by upregulating ZEB1 [162] and lncRNA LINC00943 [163]. Dual oncogenic and tumor suppressive effects of miR-103 were elucidated in gastric cancer. It was found that overexpressed caveolin-1 and RAB10 were targets for suppressive miR-103 [164, 165] while miR-103 acting as oncogenic by downregulation of KLF4 [166]. lncRNA LINC00152 acting as oncogenic by sponging miR-103 and upregulation of RAB10 [165]. miR-105 inhibits gastric cancer cell metastasis, by targeting SOX9 and YY1 [167, 168, 169]. miR-106 play an oncogenic role in gastric cancer [170]. lncRNA GPC5-AS1 acting as tumor suppressor for gastric cancer via sponging miR-106 and upregulation of GPC5 [137]. Like miR-103, miR-107 has onogenic and tumor suppressive effects in gastric cancers, oncogenic by downregulation of PTEN [171], NF1 [172], and HIF-1α [173] suppressive by targeting BDNF [174]. lncRNA ZFR and PCAT18 counteracting oncogenic effect of miR-107 by upregulation of PTEN [171, 175]. Suppresivity of miR-122 may be linked to their target downregulation including DUSP4 [176], LYN [177], MYC [178], MMP-9 [179], GIT-1 [180], and VEGFD [181] while their effect can be sponged by lncRNA LINC01296, CRART16, and promoting metastasis by upregulation of MMP-9 and VEGFD respectively [179181]. Same thing for miR-124, they inhibit gastric cancer by downregulating many oncogenes like SPHK1 [182], ROCK1 [183], RAC1 and SP1 [184], EZH2 [185186], DNMT3B [187], and ITGB3 [188]. lncRNA MALAT1, LINC00511, LINC00240, and HOXA11-AS were overexpressed in gastric cancer as oncogene promoting cancer cell viability, proliferation, and metastasis via sponging miR-124 and upregulating EZH2, DNMT3B and ITGB3 respectively [185, 186, 187, 188]. Tumor suppresivity of miR-125 on gastric cancers was attributed to downregulation of many proteins inhibiting proliferation and metastasis: MCL1, BRMS1, VEGF-A, and HER2 [189, 190, 191, 192], while lncRNA PVT1 was the only oncogenic ncRNA sponging miR-125 in gastric cancer [193]. Tumor suppressor miR-126 can inhibit proliferation and metastasis of gastric cancers by downregulation of CRKL, VEGF-A, CXCR4, ADAM9, BRCC3, and PIK3R2 [194, 195, 196, 197, 198, 199] while TMPO-AS1 and HOTAIR were two oncogenic lncRNA promoting invasion and metastasis by upregulation of BRCC3 and PIK3R2, and sponging miR-126 [198, 199]. As tumor suppressor acting to downregulate MAPK4, WNT7a, SORT1, and MTDH by miR-127 and inhibiting gastric cancer invasion [200, 201, 202, 203]. SORT1 and MTDH can be upregulated by sponging miR-127 by lncRNA circ_0110389 and circALPL respectively [202, 203]. Four lncRNA were found to be oncogenic and sponging the tumor suppressor miR-128 and upregulating their targets leading to promoting gastric cancer proliferation and metastasis: lncRNA CCL2 with PARP2, lncRNA HCP5 with HMGA2, lncRNA PCAT1 with ZEB1, and lncRNA LINC01091 with ELF4 [204, 205, 206, 207]. Additional 4 oncogenic lncRNA were upregulated in gastric cancer tissues and downregulated miR-129: GACAT2, GACAT3, AC130710, and PCGEM1, which upregulate P4HA2 [208, 209, 210]. Oncogenic miR-130 promotes gastric cancer invasion and metastasis by downregulation of TGFβR2, C-MYB, and GCNT4 [211, 212, 213] while lncRNA MRPL39 acts to suppress the metastasis by sponging miR-130 [214]. Tumor suppressor miR-132 inhibits gastric tumor invasiveness and metastasis via downregulation of MUC13, CD44 and fibronectin1 (FN1), KIF21B, and PXN [215, 216, 217, 218], while lncRNA XIST can sponge miR-132 and upregulate PXN [218]. miR-134 and their lncRNA can have dual effects as tumor suppressor or oncogene and vice versa. By targeting and downregulation of GOLPH3, YY1 and YWHAZ [219, 220, 221] miR-134 acting as gastric cancer suppressor while acting as oncogene to deactivate PTEN while lncRNA circPTK2 can sponge miR-134 to activate PTEN inhibiting proliferation and metastasis [222]. Inversely lncRNA LUCAT1 can act as oncogene sponging suppressor miR-134 and upregulation of YWHAZ [221]. Oncogenic miR-135 can downregulate E2F1 and DAPK2 [223] and upregulate WNT [224] while miR-135 can act as gastric cancer suppressor downregulating SMAD2 [225]. Gastric cancer metastasis and invasion can be promoted by sponging of miR-136 by lncRNA circ_0110389 and circ_100876 leading to upregulation of SORT1 and MIEN1 respectively [202, 226]. Sponging of miR-137 by lncRNA like DSCR8, NCK1-AS1, and circHECTD1 can promote invasion and proliferation of gastric cancer by upregulation of CDC42, NUP43, and PBX3 respectively [227, 228, 229]. miR-138 inhibits gastric cancer vitality and progression by downregulation of ITGA2, PLAU, FOXC1, and SIRT2, which can be upregulated after sponging miR-138 by lncRNA UBE2CP3, TRPM2-AS, MCM3AP-AS1, and LINC00152 respectively [230, 231, 232, 233]. Same miR-138, miR-139 is tumor suppressor ncRNA inhibiting of tumorgenicity and their effect can be sponged by lncRNA, which promote tumorigenicity via upregulation of MYB, MMP11, PRKAA1, ELK1, and SOX4 by lncRNA SNHG3, CTBP1-AS2, LINC00152, Circ-PTPDC1, and circ_0000218 respectively [234, 235, 236, 237, 238]. Tumor suppresivity of miR-140 in gastric cancer was achieved via decreasing the expression of ATG5, SOX4, ADAM10, and NDRG3. Inverse effect (oncogenic) on gastric cancer can be accomplished by lncRNA CCAT1, TMPO-AS1, SNHG1, and SNHG20, which upregulate previously mentioned proteins respectively [239, 240, 241, 242] (Tables 4 and 5).

miRNAExpression in ESCCRole in ESCCTarget geneRef.
miR-1DownregulatedTumor-suppressorMET[95]
miR-7DownregulatedTumor-suppressorEGFR[243]
miR-9OverexpressedOncogenicCDX2[99]
miR-9DownregulatedTumor-suppressorMYH9[100]
miR-17OverexpressedOncogenicPTEN, EGR2[101, 102]
miR-18OverexpressedOncogenicIRF2[104]
miR-19OverexpressedOncogenicNA[106]
miR-20OverexpressedOncogenicNA[106]
miR-21OverexpressedOncogenicPTEN, RECK, and PDCD4[107]
miR-22DownregulatedTumor-suppressorMMP14, NET1, and Snail[109]
miR-24OverexpressedOncogenicCDKN1B and CHEK1[110]
miR-25OverexpressedOncogenicFOXO3[111]
miR-26OverexpressedOncogenicPTEN, EZH2[113]
miR-27OverexpressedOncogenicHOXA10[115]
miR-28DownregulatedTumor-suppressorAKT[116]
miR-29DownregulatedTumor-suppressorCCND2, MMP2[118]
miR-30DownregulatedTumor-suppressorbeclin-1, Snail, and ETS2[120, 121, 123]
miR-30OverexpressedOncogenicP53[124]
miR-31DownregulatedTumor-suppressorE2F2s, RhoA, and ITGA5[125, 126, 127]
miR-32OverexpressedOncogenicKLF4, KLF2[128, 244]
miR-33DownregulatedTumor-suppressorCDK6, CCND1, and PIM1[129]
miR-34DownregulatedTumor-suppressorBcl-2, Notch, and HMGA2[130]
miR-43OverexpressedOncogenicVEZT[131]
miR-92DownregulatedTumor-suppressorEP4, Notch1, SOX4, and FBXW7[132, 133, 134]
miR-93OverexpressedOncogenicIFNAR1, PTEN GPC5, and PTG3[135, 136, 137, 138]
miR-95OverexpressedOncogenicEMP1[139]
miR-95DownregulatedTumor-suppressorSlug[140]
miR-96OverexpressedOncogenicZDHHC5, KIF26A, and FOXO3[141, 142]
miR-98DownregulatedTumor-suppressorBCAT1, Treg, and CCND2[143, 144, 145]
miR-100DownregulatedTumor-suppressorBMPR2, ZBTB7A[146, 147, 148]
miR-100OverexpressedOncogenicp53, HS3ST2[149, 150]
miR-101DownregulatedTumor-suppressorANXA2, ZEB1, SOCS2, PI3K/AKT/mTOR, EZH2, and AMPK[155, 156, 157, 158, 159]
miR-103DownregulatedTumor-suppressorCaveolin-1, RAB10[164, 165]
miR-103OverexpressedOncogenicKLF4[166]
miR-105DownregulatedTumor-suppressorSOX9, YY1[167, 168, 169]
miR-106OverexpressedOncogenicNA[170, 245]
miR-107OverexpressedOncogenicPTEN, NF1, and HIF1α[171, 172, 173]
miR-107DownregulatedTumor-suppressorBDNF[174]
miR-122DownregulatedTumor-suppressorDUSP4, LYN, MYC, MMP-9, and GIT-1[176, 177, 178, 179, 180]
miR-124DownregulatedTumor-suppressorSPHK1, ROCK1, RAC1, and SP1[182, 183, 184]
miR-125DownregulatedTumor-suppressorMCL1, BRMS1, VEGF-A, and HER2[189, 190, 191, 192]
miR-126DownregulatedTumor-suppressorCRKL, VEGF-A, CXCR4, ADAM9, BRCC3, and PIK3R2[194, 195, 196, 197, 198, 199]
miR-127DownregulatedTumor-suppressorMAPK4, WNT7a, SORT1, and MTDH[200, 201, 202, 203]
miR-128DownregulatedTumor-suppressorPARP2, HMGA2, ZEB1, and ELF4[204, 205, 206, 207]
miR-129DownregulatedTumor-suppressorP4HA2[210]
miR-130OverexpressedOncogenicTGFβR2, C-MYB, and GCNT4[211, 212, 213]
miR-132DownregulatedTumor-suppressorMUC13, CD44, fibronectin1 (FN1), KIF21B, and PXN[215, 216, 217, 218]
miR-134DownregulatedTumor-suppressorGOLPH3, YY1, and YWHAZ[219, 220, 221]
miR-134OverexpressedOncogenicPTEN[222]
miR-136DownregulatedTumor-suppressorSORT1, MIEN1[202, 226]
miR-137DownregulatedTumor-suppressorCDC42, NUP43, and PBX3[227, 228, 229]
miR-138DownregulatedTumor-suppressorITGA2, PLAU, FOXC1, and SIRT2[230, 231, 232, 233]
miR-139DownregulatedTumor-suppressorMYB, MMP11, PRKAA1, ELK1, and SOX4[234, 235, 236, 237, 238]
miR-140DownregulatedTumor-suppressorATG5, SOX4, ADAM10, and NDRG3[239, 240, 241, 242]

Table 4.

Oncogenic/tumor suppressor miR among stomach cancer.

lncRNAExpression of lncRNA in Stomach cancerTarget miRTarget geneRef.
LINC00242OverexpressedmiR-1MET[97]
UCA1OverexpressedmiR-7EGFR[98]
HULCOverexpressedmiR-9MYH9[100]
HOTAIRM1DownregulatedmiR-17PTEN[101]
LINC01939DownregulatedmiR-17EGR2[102]
NEAT1OverexpressedmiR-17GSK3β[103]
CASC2DownregulatedmiR-19NA[105]
MEG3DownregulatedmiR-21PTEN[108]
CTC-497E21.4OverexpressedmiR-22NET1[109]
GATA6-ASDownregulatedmiR-22FOXO3[112]
TET1–3DownregulatedmiR-26EZH2[114]
LOC400043OverexpressedmiR-28AKT[117]
MEG3OverexpressedmiR-29CCND2, MMP2[119]
PVT1OverexpressedmiR-30Snail[121]
HNF1A-AS1OverexpressedmiR-30PI3K/AKT[122]
DLEU2OverexpressedmiR-30ETS2[123]
MIR31HGOverexpressedmiR-31E2F2s, RhoA, and ITGA5[127]
SNHG5DownregulatedmiR-32KLF4[128]
PITPNA-AS1OverexpressedmiR-92SOX4[133]
MT1JPOverexpressedmiR-92FBXW7[134]
PTENP1DownregulatedmiR-93PTEN, GPC5, and PTG3[136, 137, 138]
TTTY15OverexpressedmiR-98CCND2[145]
HAGLROSOverexpressedmiR-100mTORC1 signaling pathway[151]
MIR100HGOverexpressedmiR-100PI3K/AKT/mTOR pathway[152, 153, 154]
LINC01303OverexpressedmiR-100EZH2[159]
SPRY4-IT1OverexpressedmiR-100AMPK[160]
XISTOverexpressedmiR-100EZH2[161]
SNHG6OverexpressedmiR-100ZEB1[162]
LINC00943OverexpressedmiR-100NA[163]
LINC00152OverexpressedmiR-103RAB10[165]
GPC5-AS1DownregulatedmiR-106GPC5[137]
ZFRDownregulatedmiR-107PTEN[171]
PCAT18DownregulatedmiR-107PTEN[175]
LINC01296OverexpressedmiR-122MMP-9[179]
CRART16OverexpressedmiR-122VEGFD[180]
MALAT1OverexpressedmiR-124EZH2[185]
LINC00511OverexpressedmiR-124EZH2[186]
LINC00240OverexpressedmiR-124DNMT3B[187]
HOXA11-ASOverexpressedmiR-124ITGB3[188]
PVT1OverexpressedmiR-125NA[193]
BRCC3OverexpressedmiR-126BRCC3[198]
PIK3R2OverexpressedmiR-126PIK3R2[199]
circ_0110389OverexpressedmiR-127SORT1[202]
circALPLOverexpressedmiR-127MTDH[203]
CCL2OverexpressedmiR-128PARP2[204]
HCP5OverexpressedmiR-128HMGA2[205]
PCAT1OverexpressedmiR-128ZEB1[206]
LINC01091OverexpressedmiR-128ELF4[207]
GACAT2,OverexpressedmiR-129NA[208]
GACAT3OverexpressedmiR-129NA[208]
AC130710OverexpressedmiR-129NA[209]
PCGEM1OverexpressedmiR-129NA[210]
MRPL39DownregulatedmiR-130NA[214]
XISTOverexpressedmiR-132PXN[218]
circPTK2DownregulatedmiR-134PTEN[222]
LUCAT1OverexpressedmiR-134YWHAZ[221]
circ_0110389OverexpressedmiR-136SORT1[202]
circ_100876OverexpressedmiR-136MIEN1[226]
DSCR8OverexpressedmiR-137CDC42[227]
NCK1-AS1OverexpressedmiR-137NUP43[228]
circHECTD1OverexpressedmiR-137PBX3[229]
UBE2CP3OverexpressedmiR-138ITGA2[230]
TRPM2-ASOverexpressedmiR-138PLAU[231]
MCM3AP-AS1OverexpressedmiR-138FOXC1[232]
LINC00152OverexpressedmiR-138SIRT2[233]
SNHG3OverexpressedmiR-139MYB[234]
CTBP1-AS2OverexpressedmiR-139MMP11[235]
LINC00152OverexpressedmiR-139PRKAA1[236]
Circ-PTPDC1OverexpressedmiR-139ELK1[237]
circ_0000218OverexpressedmiR-139SOX4[238]
CCAT1OverexpressedmiR-140ATG5[239]
TMPO-AS1OverexpressedmiR-140SOX4[240]
SNHG1OverexpressedmiR-140ADAM10[241]
SNHG20OverexpressedmiR-140NDRG3[242]

Table 5.

Oncogenic/tumor suppressor lncRNA among stomach cancer.

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2. Conclusion

The current review concludes the vital role of ncRNA (both miRNA and lncRNA) in some digestive system tumors either as an oncogene-promoting cancer viability, invasiveness, proliferation, and metastasis or as a tumor suppressor inhibiting tumorigenicity or inducing apoptosis.

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Conflict of interest

There is no “conflict of interest” for this work.

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Written By

Hussein Al-Dahmoshi, Noor Al-Khafaji, Moaed E. Al-Gazally, Maha F. Smaism, Zena Abdul Ameer Mahdi and Suhad Y. Abed

Submitted: June 17th, 2022 Reviewed: August 25th, 2022 Published: October 7th, 2022