Topic review

Role of Non-Coding RNAs and Metabolism in Lung Cancer

Subjects: Oncology & Oncogenics View times: 139

Abstract

Ruben Mercado Santos and Cerena Moreno contributed equally to this work.

Lung cancer is one of the deadliest forms of cancer affecting society today. Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), through the transcriptional, post-transcriptional, and epigenetic changes they impose, have been found to be dysregulated to affect lung cancer tumorigenesis and metastasis. This review will briefly summarize non-coding RNAs-mediated signaling pathways and metabolic pathways involved in lung cancer. The targeting of cancer cells with non-coding RNAs can affect vital metabolic and cell signaling pathways, which as a result can potentially have a role in cancerous and pathological processes. By further understanding non-coding RNAs, researchers can work towards diagnoses and treatments to improve early detection and clinical response.

For cancer to effectively initiate proliferation and tumorigenicity, various metabolic pathways are altered to support the needs of the cancer cells. When studying the metabolism in lung cancer, there are distinct signaling pathways including apoptotic, growth promoting, and growth inhibiting that must be considered[1]. Out of these pathways the most notable are EGFR, MET, PI3K/Akt/mTOR, Ras/Raf/Mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK), and Wnt/β-catenin[2](Table 1; Figure 1). As a result, non-coding RNAs affecting the cell signaling pathways also have a role in regulation of different cell metabolism cycles including glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), and lipid synthesis. Targeting of the enzymes within these metabolic cycles by non-coding RNAs has been reported, which could suggest alteration of cellular processes by controlling non-coding RNA regulation. miR-125a and miR-143 have been reported to target the glycolytic enzyme hexokinase 2 (HK2) by downregulation[3]. As for lactate dehydrogenase A, an enzyme in glycolysis responsible for imitation of lactate production, has targets serving as negative regulators include miR-200c[4], miR-33b[5], and miR-449a[6]. Additionally, lncRNA CRYBG3 overexpression has been reported to be associated with LDHA upregulation[7]. Glycolysis harbors another important pathway known as the PPP. Singh et al. looked at regulation of miR-1 and miR-206 by nuclear factor erythroid-2-related factor 2 (NRF2) which serves as a tumor initiator once activated[8]. Once these miRNAs are regulated, progression of the PPP and TCA cycling can occur. As for the TCA cycle, enzymes such as succinate dehydrogenase (SDH), isocitrate dehydrogenase (IDH), and malate dehydrogenase (MDH) have been identified as targets for various miRNAs (Figure 2). Upregulation of miR-147b repressed enzymatic activity of SDH, initiating a pseudohypoxia signaling response[9]. Similarly, upregulation of miR-210 decreased enzymatic activity of SDHD and furthered activity of HIF-1α[10]. This idea of adaptation to stress environments is also present via miR-183 and IDH2 regulation[11]. Vohwinkel et al. compared IDH2 response to elevated CO2 with IDH2 response to upregulated miR-183 in epithelial lung cancer cells and found that both downregulated IDH2[11]. The adaptation of cancer cells to the stress environment by reprogramming metabolic processes could serve as a leading cause of witnessed therapeutic resistance, furthering cancer’s progression. Complexes, such as the miR-182-PDK4 axis, have been reported to regulate pyruvate dehydrogenase which is an essential part of TCA cycling and lipogenesis[12]. Other important targets include miR-22 downregulation on ATP citrate lyase (ACLY), which allowed for ACLY-mediated lipogenesis and caused increased metastatic effects[13]. Enzymatic activity of MDH1 can be altered as well with miR-126-5p in NSCLC, and with greater doses initiated cell toxicity[14]. The role of non-coding RNAs as regulators in a variety of pathways makes them an important part of studying tumor initiation and progression.

Table 1. Non-coding RNAs that affect cell signaling and metabolic pathways.

Name of ncRNA

Type of ncRNA

Targets

Signaling Pathway

Metabolic Pathway

References

miR-21

miRNA

PTEN

Ras/Raf/MEK/ERK, PI3K/Akt/mTOR

Glycolysis, Glucose-mediated TCA Cycle

[15]

miR-147b

miRNA

VHL, SDH

EGFR

ETC, TCA Cycle

[9]

miR-34a

miRNA

EGFR

Ras/Raf/MEK/ERK, PI3K/Akt/mTOR

Glycolysis

[16]

miR-329

miRNA

MET

Ras/Raf/MEK/ERK, PI3K/Akt/mTOR

N.A.

[17]

miR-139-5p

miRNA

MET

Ras/Raf/MEK/ERK, PI3K/Akt/mTOR

N.A.

[18]

miR-206

miRNA

MET

Ras/Raf/MEK/ERK, PI3K/Akt/mTOR

N.A.

[19]

miR-148a-3p

miRNA

SOS2

Ras/Raf/MEK/ERK

N.A.

[20]

miR-193a-3p

miRNA

KRAS

Ras/Raf/MEK/ERK

N.A.

[21][22]

miR-181a-5p

miRNA

KRAS

Ras/Raf/MEK/ERK

N.A.

[23]

miR-30c

miRNA

BID, NF1

Ras/Raf/MEK/ERK

Glucose-mediated TCA Cycle

[24]

Orilnc1

lncRNA

N.A.

Ras/Raf/MEK/ERK

N.A.

[25]

miR-494-3p

miRNA

PTEN

PI3K/Akt/mTOR

Glycolysis

[26]

miR-19a

miRNA

MET

PI3K/Akt/mTOR

N.A.

[27]

miR-409-3p

miRNA

MET

PI3K/Akt/mTOR

N.A.

[28]

ROR

lncRNA

N.A.

PI3K/Akt/mTOR

Glycolysis

[29]

miR-142-3p

miRNA

HMGB1

PI3K/Akt/mTOR

Glycolysis

[30]

miR-221

miRNA

PTEN

PI3K/Akt/mTOR

Glycolysis

[31]

miR-124

miRNA

GLUT1, HK2

PI3K/Akt/mTOR

Glycolysis

[32]

miR-182

miRNA

HIF1AN

PI3K/Akt/mTOR

ETC, TCA Cycle

[33]

lncRNA-NEF

lncRNA

GLUT1

PI3K/Akt/mTOR

Glycolysis

[34]

miR-145-3p

miRNA

PDK1

PI3K/Akt/mTOR

N.A.

[35]

miR-487b

miRNA

KRAS, Wnt5a, MYC

Wnt/β-Catenin

N.A.

[36]

miR-203

miRNA

FZD2

Wnt/β-Catenin

N.A.

[37]

miR-548b

miRNA

CCNB1

Wnt/β-Catenin

N.A.

[38]

miR-374a

miRNA

Wnt5a

Wnt/β-Catenin

N.A.

[38]

AK126698

lncRNA

FZD8

Wnt/β-Catenin

ETC

[39]

LINC00673-v4

lncRNA

DDX3

Wnt/β-Catenin

N.A.

[40]

miR-660

miRNA

MDM2

p53

N.A.

[41]

miR-98

miR-453

miRNA

TP53

p53

N.A.

[42]

circ-MTO1

circRNA

miR-17 ┤QKI-5

Notch

N.A.

[43]

circRNA_103809

circRNA

miR-4302 ┤ZN121

MYC

N.A.

[44]

miR-342-3p

miRNA

E2F1

MYC

N.A.

[45]

miR-451a

miRNA

MYC

MYC

N.A.

[46]

PART1

lncRNA

miR-635

JAK/STAT

N.A.

[47]

miR-135

miRNA

TRIM16

JAK/STAT

N.A.

[48]

┤, inhibition. Abbreviations: AKT serine/threonine kinase (AKT), BH3-interacting domain death agonist (BID), C-X3-C motif chemokine receptor 1 (CX3CR1), DEAD-box helicase 3 X-linked (DDX3), epidermal growth factor receptor (EGFR), E2F transcription factor 1 (E2F1), electron transport chain (ETC), frizzled class receptor 2 (FZD2), frizzled class receptor 8 (FZD8), glucose transporter 1 (GLUT1), hypoxia inducible factor 1 subunit alpha inhibitor (HIF1AN), high mobility group box 1 (HMGB1), janus kinase (JAK), mouse double minute 2 (MDM2), mechanistic target of rapamycin kinase (mTOR), neurofibromin 1 (NF1), prostate androgen-regulated transcript 1 (PART1), phosphoinositide-dependent protein kinase-1 (PDK1), phosphatase and tensin homolog (PTEN), quaking homolog (QKI-5), sirtuin 1 (SIRT1), son of sevenless homolog 2 (SOS2), signal transducer and activator of transcription (STAT), tricarboxylic acid cycle (TCA Cycle), tumor protein p53 (TP53), Wnt family member 5a (Wnt5a), wingless-type (WNT), not available (N.A.).

Ijms 21 02774 g002 550

Figure 1. Interactions among cell signaling pathways and non-coding RNAs. →, promotion; ┤, inhibition; ↷/⤾, guanine nucleotide exchange reactions. Abbreviations: AKT serine/threonine kinase (AKT), adenomatous polyposis coli (APC), BH3-interacting domain death agonist (BID), cyclin B1 (CCNB1), casein kinase I (CKI), DEAD-box helicase 3 X-linked (DDX3), disheveled (DVL), epidermal growth factor receptor, frizzled class receptor 2 (FZD2), frizzled class receptor 8 (FZD8), glycogen synthase kinase 3 (GSK3), hypoxia inducible factor 1 subunit alpha (HIF1α), hypoxia inducible factor 1 subunit alpha inhibitor (HIF1AN), IκB kinase (IKK), matrix metallopeptidase 9 (MMP9), MET proto-oncogene receptor tyrosine kinase (MET), mechanistic target of rapamycin kinase (mTOR), neurofibromin 1 (NF1), nuclear factor kappa-light-chain-enhancer of activated B (NF-κB), phosphoinositide-dependent protein kinase-1 (PDK1), sirtuin 1 (SIRT1), son of sevenless homolog 2 (SOS2), wingless-type (WNT).

Ijms 21 02774 g003 550

Figure 2. Metabolic pathways including glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, and lipid synthesis with target non-coding RNAs. →, promotion; ┤, inhibition; ⟳, metabolic reactions of the tricarboxylic acid cycle. Abbreviations: 3-Phosphoglyceric acid (3PG), AKT serine/threonine kinase (AKT), ATP citrate lyase (ACLY), aconitase (ACO), ⍺-Ketoglutarate dehydrogenase (⍺-KGDH), citrate synthase (CS), fructose 6-phosphate (F6P), fructose bisphosphatase (FBP), fumarase (FH), glucose 6-phosphate (G6P), glucose-6-phosphate dehydrogenase (G6PD), histone deacetylase 4 (HDAC4), glucose transporter 1 (GLUT1), hexokinase 2 (HK2), isocitrate dehydrogenase (IDH), lactate dehydrogenase A (LDHA), malate dehydrogenase (MDH), nuclear factor erythroid-2-related factor 2 (NRF2), phosphoenolpyruvate (PEP), phosphofructokinase-1 (PFK), phosphogluconate dehydrogenase (PGD), pyruvate kinase M1/2 (PKM2), pentose phosphate pathway (PPP), succinyl-CoA synthetase (SCS), succinate dehydrogenase (SDH), transketolase (TKT), wingless-type (WNT).

EGFR

EGFR is a transmembrane protein. In different types of cancers, the mutation can occur in different spots and for NSCLC it is in the kinase domain[49]. In order to reduce effect of these mutations, therapies focus on targeting with a tyrosine kinase inhibitor (TKI). Due to the position of EGFR on the cell, it serves as an activator site for multiple signaling pathways including MAPK, PI3K/Akt, and PLC-γ1-PKC[49]. Chou and colleagues found that with the overexpression of miR-7, a miRNA induced by EGFR, demonstrated an increase in cell proliferation and tumor growth rate through the Ras/ERK/Myc pathway[50]. EGFR can be directly targeted by miR-34a through upregulation due to the tumor suppressive abilities of miR-34a[16]. EGFR can also dysregulate non-coding RNAs. miR-21 have shown upregulation in NSCLC, demonstrating how EGFR can function as a regulator for potential tumor progressive non-coding RNAs[51]. Alternatively, regulation of crosstalk between pathways has been noted through miR-205[52]. Migilore et al. investigated MET-TKI resistance and found that with overexpression of miR-205, a target of ERBB receptor feedback inhibitor 1, induced greater EGFR activity[52]. This could suggest the need for co-targeting of EGFR-associated pathways to prevent tumor progression. The targeting of specific non-coding RNAs related to EGFR expression can serve as therapy options in order to inhibit prominent cell signaling pathways present in lung cancer. EGFR has a strong link to glycolysis, which is a precursor to multiple metabolic pathways. Kim et al. looked at how glycolysis was enhanced due to increased glucose uptake and lactate production in order to keep the EGFR mutant NSCLC nourished[53]. As a result of high glucose production, ATP levels were increased which suggests glucose fed TCA cycling[53]. By altering metabolism, cancer cells are able to manage themselves and pursue oncogenic processes, so by targeting of specific receptors or enzymes by non-coding RNAs could inhibit these processes and force cancer cells to find alternative resources or simply die.

MET

The MET signaling pathway can be altered through overexpression of MET and/or its ligand the hepatocyte growth factor, and genetic variation of the MET gene, both common in oncogenic processes[54]. Similar to the EGFR, through the activation of MET there are important downstream pathways including MAPK and PI3K that can be activated[55]. Sun and colleagues looked at miR-329 due to its presence in other cancers, and they found that it targets MET to induce negative regulation, which as a result inhibits proliferation and tumorigenesis of NSCLC[17]. Sun et al. has also noted similar findings with miR-139-5p[18] and miR-206[19]. Others have found that targeting of c-MET with miR-19a [209] and miR-409-3p[28] could inhibit downstream signaling of the Akt signaling pathway as well. Due to crosstalk between KRAS/MET and EGFR/MET, dual targeting of these signaling pathways via non-coding RNAs could potentially predict drug sensitivity, biomarker potential, and prognostic value[56][57].

PI3K/Akt/mTOR

The responsibility of this cell signaling pathway is to regulate metabolism and delegate where glucose should be maintained[58]. Initiation of this pathway is through the activation of membrane receptors including tyrosine kinases (TK) such as EGFR, FGFR, HER2, IGFR-1, PDGFR, and VEGFR[59]. Shi and colleagues found that the lncRNA ROR directly inhibits this pathway and could demonstrate increased sensitivity to cisplatin in NSCLC patients[29]. The role of various lncRNA in regard to lung tumor development and progression is still subject for further study. As for the role of miRNA, it was found that the overexpression of miR-296-3p reduced the level of phosphorylation in this pathway without reducing mRNA expression by targeting apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1), therefore possibly inhibiting the pathway’s progression particularly in NSCLC[60]. Additionally, miR-296-3p has been reported to have lower levels of expression in comparison to normal lung epithelial cells, and it played a role in inhibiting NSCLC cell proliferation as well as cisplatin sensitivity by targeting C-X3-C motif chemokine receptor 1(CX3CR1) which is upstream of PI3K signaling[61]. miR-142-3p was found to have an association between the PI3K/Akt/mTOR pathway and high mobility group box 1 (HMBG1) induced autophagy, a process of cellular degradation that if in a high presence can demonstrate conflicting results such as promoting tumor survival versus preventing tumorigenesis[30][62]. In this case, NSCLC autophagy was inhibited via the overexpression of miR-142-3p[30]. Another primary target within the PI3k/Akt/mTOR signaling pathway is PTEN. PTEN is a protein found to terminate hyperactive signaling of PI3K, and the loss of its function has been noted in various human cancers[63]. Common non-coding RNA targets of PTEN in lung carcinoma through upregulation include miR-21[64], miR-205[65], miR-221[31], and miR-494[26]. With targeting of these specific miRNAs, dependent on whether they deactivate or activate PTEN, can work towards understanding the treatments necessary to regulate the PI3K/Akt/mTOR pathway. Non-coding RNAs targeting Akt signaling can also dysregulate cell metabolism. Makinoshima et al. found that there was a link between the PI3K/Akt/mTOR pathway and aerobic glycolysis as well as maintenance of glucose transporter 1 (GLUT1) through optimal membrane localization specifically in EGFR mutated lung adenocarcinoma cells[66]. GLUTs are responsible for glucose intake and with increased expression through this pathway can facilitate increased glycolytic activity such as ATP consumption and ACLY stimulation, essentially serving as a precursor for lipid synthesis[67]. Zhao et al. found that with the overexpression of miR-124, GLUT1, and HK2 expression were reduced[32]. Similarly, it was reported that overexpression of lncRNA-NEF reduced expression of GLUT1, resulting in the inhibition of glucose uptake in NSCLC[34]. Targeting GLUTs by non-coding RNAs could potentially have a role in decreasing tumorigenesis. Another contributing factor to metabolism via PI3K/Akt/mTOR signaling is through HIF-1α, mediated by upstream mTOR[68]. Increased HIF-1α can initiate tumorigenesis in lung cancer, but by targeting of VHL by miR-147b[9] and HIF1AN by miR-182[33], regulation can be reduced to prevent this initiation. HIF-1α can also modulate lncRNA HOTAIR to promote lung tumorigenesis in hypoxic conditions[69][70] and miR-210-3p to prevent HIF-1α degradation via suppression of SDHD enzymatic activity[10]. Focusing on non-coding RNA markers contributory to glucose metabolism and hypoxic response can help better understand how pathway crosstalk influences cell processes leading to tumorigenesis and progression.

Ras/Raf/MEK/ERK (MAPK)

The MAPK signaling pathway consists of a variety of interconnected pathways that work to regulate growth, proliferation, and survival of the cells, initiated by growth factor receptors, similar to that of the PI3K/Akt/mTOR pathway[71]. Through the inhibition of mTOR/mTORC1, the Ras/Raf/MEK/ERK pathway can be activated through Ras[72]. The MAPK pathway can be activated by decreasing mRNA translation in SIRT1 via miR-520c and miR-373[73]. The crosstalk between the two pathways perhaps demonstrates how multiple pathways become involved in tumorigenesis and proliferation, and by targeting one can reduce activation of the other. Xie and colleagues looked at miR-148a-3p, a tumor growth suppressor found in NSCLC, and found that it had a role in MAPK/ERK inhibition via overexpression which led to decreased presence of son of sevenless homolog 2 (SOS2) and consequently inhibited Ras activation[20]. Alternatively, targeting activated KRAS with overexpression of tumor suppressors miR-193a-3p[21][22] and miR-181a-5p[23][74] could potentially inhibit further progression of tumor growth. Homogenous KRAS G12D mutant, a common mutation causing dysregulation of the MAPK pathway, has been reported to favor glucose fueled TCA cycling due to glucose metabolic reprogramming and reactive oxygen species (ROS) management, leading to increased malignancy[75]. The interplay between miRNA and ROS in cancer treatment response has been discussed in recent reviews[76][77]. Non-coding RNAs such as miR-21 and miR-30c have shown upregulation with KRAS G12D overexpression, which as a result enhance regulation of Ras downstream pathways[24]. In contrast, a negative regulator of Ras includes the let-7 family which acts as a tumor suppressive miRNA and inhibits downstream signaling[78]. Alternatively, the expression of non-coding RNAs can be regulated through the signaling pathway itself. As noted by Zhang et al., with the inhibition of the MAPK pathways, expression of Ornlnc1, a highly expressed lncRNA in BRAF mutated cancers, was decreased[25]. As a result, this subsequently reduced cancer cell growth in vivo and in vitro.

Wnt/β-Catenin

The Wnt/β-catenin (canonical) pathway holds the responsibility of determining cell polarity, rate of proliferation, and the fate of the cell[79]. Through this pathway, mutation at and surrounding the β-catenin site is most common in cancers, but in regard to lung cancer, its distinguishing factor is based on alterations to various Wnt proteins including Wnt-1–5a, frizzled class receptor 8 (FZD8), and the gene β-catenin[79][80]. miR-487b and miR-203 have been noted to work as tumor suppressive miRNAs in lung cancer by targeting KRAS, WNT5A, SUZ12, MYC, and BMI1 (miR-487b)[36] and FZD2 (miR-203)[37]. Targeting of CCNB1 by miR-548b and Wnt5a by miR-374a have also been reported in lung cancer cell lines, with both serving as tumor repressors[38]. Other lncRNAs that work as a suppressor include MEG3, interaction with p53 to downregulate β-catenin[81], and AK126698, negative regulation of FZD8[39]. Alternatively, Guan and colleagues found that the overexpression of the lncRNA LINC00673-v4 was found to activate the Wnt/β-catenin pathway, noted by the enhanced interaction between DDX3 and CK1ε essentially leading to enhanced signaling of the pathway in lung adenocarcinoma cells[40]. With the overexpression of β-catenin and β-catenin transcriptional activity by SDH5 (ETC component) inhibition, cancer metabolism can be altered through the mediation of Wnt EMT and metastasis[82]. β-catenin activation is mediated through the GSK-3β enzyme which in turn can be altered through targeting by SDH5[82]. It has been reported that Wnt/β-catenin can be regulated through the inactivation of the DVL2-NRX complex formation by elevating ROS (Ca2+ mediated), which can additionally cause accumulation of nuclear β-catenin in human neural progenitor cells[83][84]. Accumulation of β-catenin through glucose has also been reported to enhance the signaling pathway and as a result increase the risk of cancer development[85].

The entry is from 10.3390/ijms21082774

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