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MicroRNAs and Lung Cancer: A Review Focused on Targeted Genes

  • Yao-Hui Wang1,2,3,
  • Zhi-Ruo Zhu1,2,3,
  • De Tong1,2,3,
  • Rui Zhou1,2,3,
  • Kui Xiao1,2,3,*  and
  • Ling Peng4,* 
Exploratory Research and Hypothesis in Medicine   2021;6(2):67-76

doi: 10.14218/ERHM.2020.00058

Received:

Revised:

Accepted:

Published online:

 Author information

Citation: Wang YH, Zhu ZR, Tong D, Zhou R, Xiao K, Peng L. MicroRNAs and Lung Cancer: A Review Focused on Targeted Genes. Explor Res Hypothesis Med. 2021;6(2):67-76. doi: 10.14218/ERHM.2020.00058.

Abstract

Lung cancer is the leading cause of cancer morbidity and mortality. Surgery, chemotherapy and radiotherapy techniques have been developed over many years, and anti-angiogenic therapy, molecular targeted therapy and immune-checkpoint inhibitors have become increasingly effective for treating lung cancer. However, the overall disease-free and survival rates of lung cancer remain quite low. MicroRNAs are small, non-coding RNAs that consist of an average of 22 nucleotide molecules. MicroRNAs play an important role in the development, progression, metastasis, diagnosis and prognosis of lung cancer. This review summarizes the recent publications abnormally expressed miRNAs and the abnormal expression of their target genes in the biological process of lung cancer. This review aims to shed light on the recent advances in this field and to provide perspectives for future directions.

Keywords

MicroRNAs, Lung cancer, Pathogenesis, Diagnosis, Therapy

Introduction

Histologically, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC is more common than SCLC, accounting for about 80% of all cases. NSCLC includes squamous cell carcinoma (SCC), adenocarcinoma, and large cell carcinoma, among which, adenocarcinoma and SCC are the most common subtypes. MicroRNAs (miRNAs) are small non-coding RNAs composed of an average of 22 nucleotides and are the most commonly studied non-coding RNAs in lung cancer.1 miRNAs mainly bind to the 3′ untranslated region of a target mRNA, which degrades target mRNA or blocks protein translation to regulate gene expression. miRNAs are involved in the regulation of the cell cycle, metastasis, angiogenesis, metabolism and apoptosis, and play an important role in the occurrence and development of tumors.

miRNAs in the development and progression of lung cancer

The occurrence and development of cancer is complex. The biological processes of cancer mainly include the occurrence of cancer, growth and metabolism, tumor microenvironment, neovascularization, tumor invasion and metastasis. A full understanding of the regulatory mechanisms and modes of action of miRNA in the occurrence and development of lung cancer may provide new strategies for the diagnosis and treatment of lung cancer. In the following sections, we will focus on the role of miRNAs in these processes.

miRNAs in the occurrence of lung cancer

The role of miRNAs in the occurrence of lung cancer manifests as targeting both oncogenes and tumor suppressor genes. The causes of lung cancer are complex and are mainly related to abnormal genes. These abnormalities usually occur in areas where genes are not stable. Studies have found that a transcriptional hyper-conserved region gene is located in an unstable genomic region associated with cancer. This super-conserved region consists of a genomic sequence family of more than 200 base pairs (bp) in length. Most transcriptional hyper-conserved region genes are not translated into proteins and act as oncogenes to promote carcinogenesis by inhibiting miRNAs.2 There are also some miRNAs involved in the development of lung cancer. Oncogenic miRNA-411 promotes lung cancer by directly targeting the inhibitory genes SPRY4 and TXNIP.3 MiR-30c and miR-21 are significantly up-regulated by the oncogene KRAS isotype, induces drug resistance and enhances cell migration or invasion by inhibiting key tumor suppressor genes such as NF1, RASA1, BID and RASSF8.4 In lung cancer cell lines, the up-regulation of miR-365a-3p targets and down-regulates USP33, and promotes the proliferation, migration, and invasion of lung cancer cells via the miR-365/USP33/SLIT2/ROBO1 axis.5 Another study found that the up-regulation of the novel miR-12528 directly targets the 3′ untranslated region of the insulin-like growth factor 1 receptor (IGF-1R) mRNA, negatively regulates proliferation, apoptosis and migration activity through hypophosphorylation of the AKT cascade, and thus inhibits tumorigenesis and metastasis in vivo.6 In addition to genetic abnormalities, external factors such as smoking also play an important role in the development of lung cancer. In fact, miRNAs have been found to be involved in the regulation of smoking-related oncogenes.7 Continuous smoking induces the development of non-small cell lung cancer by reducing the expression of microRNA, including hsa-mir-185-3p, hsa-mir-4295, hsa-mir-4288, and hsa-mir-613, associated with the ERBB pathway.8 Nicotine promotes NSCLC cell proliferation and epithelialtomesen-chymaltransition by down-regulating miR-99b and miR-192.9 In addition, miR21, which is involved in the regulation of HIF1α, plays a role in the malignant transformation of HBE cells which is induced by cigarette smoke extract through the Akt/NF-κB pathway.10 Simultaneous radiation exposure can enhance epithelial-mesenchymal transition (EMT) of A549 cells via miR3591-5p/USP33/PPM1A.11

miRNAs involved in tumor growth and metabolism

miRNAs involved in the cell cycle and apoptosis

The cell cycle is the basis of cell proliferation, which, in addition to apoptosis, are two important processes of tumor growth and are closely related to miRNAs. Of note, miR21 inhibitors promote apoptosis by inhibiting the PI3K/Akt/NF-κB signaling pathway in NSCLCs in vitro and in vivo.12 Also, miR19b enhances proliferation and apoptosis resistance through the epidermal growth factor receptor (EGFR) signaling pathway in NSCLC by targeting PP2A and BIM.13 Overexpression of miR143 significantly reduces cell proliferation and promotes apoptosis,14 and miR335-5p inhibits cell proliferation by targeting CPNE1 in NSCLC.15 Other miRNAs involved in cell cycle and apoptosis are shown in Table 1.16–28

Table 1

MicroRNAs involved in the cell cycle and apoptosis

miRNAsTargets/pathwayTumor suppressor/oncogeneLung cancer typeRef
miR485-5pIGF2BP2suppressorNSCLCHuang et al.17
miR183MTA1suppressorNSCLCYang et al.18
miR335Tra2βsuppressorNSCLCLiu et al.19
miR188MAP3K3suppressorNSCLCZhao et al.20
miR186SIRT6suppressorNSCLCRuan et al.21
miR93-5pPTEN and RB1oncogeneNSCLCYang et al.22
miR4326APC2oncogeneNSCLC/SCLCXu et al.23
miR339Skp2suppressorNSCLC/SCLCRen et al.24
miR520bHDAC4suppressorNSCLC/SCLCJin et al.25
miR628-3pHSP90suppressorNSCLC/SCLCPan et al.26
let7acyclin D1suppressorHuman Lung adenocarcinomaZhao et al.27
miR505MAP3K3suppressorNSCLCTang et al.28
miR135aIGF1suppressorNSCLCZhou et al.16

miRNAs involved in the metabolism of lung cancer

Altered metabolism is an important feature in the development of cancer. Various miRNAs can directly or indirectly participate in various metabolic processes of lung cancer cells, including glucose metabolism, amino acid metabolism and lipid metabolism,29 which provide the rapidly multiplying cells with much needed energy. At present, the research on the metabolism of miRNAs in lung cancer is mostly studied by glucose metabolism. High glucose promotes cell proliferation, migration and invasion in NSCLCs.15 By reviewing articles on miRNAs and lung cancer metabolism, it has been found that miRNAs involved in cancer metabolism mainly play a role in the regulation of a series of biological enzymes involved in the metabolic processes.30 The Warburg effect (aerobic glycolysis) is a common feature of cancer cells, which facilitates tumor cell proliferation and progression with elevated glucose uptake and lactate production.31 Lactate dehydrogenase A (LDHA), one of the subunits of lactate dehydrogenase, participates in the final step of the aerobic glycolysis process by catalyzing pyruvate into lactate. In fact, a recent study found that miR200c can inhibit the proliferation and migration of NSCLC cells by down-regulating LDHA.32 Downregulation of miR33b promotes NSCLC cell growth by reprogramming glucose metabolism.33 In NSCLC cells, down-regulated miR214 inhibits cell proliferation and glycolysis by reducing the expression of HK2 and PKM2 via the PTEN/Akt/mTOR pathway.34 Pyruvate dehydrogenase kinase 4 (PDK4) and pyruvate dehydrogenase (PDH) are important biological enzymes in sugar metabolism and fatty acid synthesis, respectively. It has been reported that the overexpression of miR-182 can regulate PDH through the miR182-PDK4 axis. PDK4 is activated and lipogenesis promotes lung cancer cell proliferation and tumor growth. Overexpression of miR182 and PDK4 knockdown significantly promotes triglyceride levels, suggesting that miR182 and PDK4 affect lipogenesis in lung cancer cells.29 Another miRNA, miR198, inhibits the proliferation of lung adenocarcinoma cells in vitro and in vivo by directly targeting SHMT1, which leads to enhanced apoptosis and leads to cell cycle arrest in lung adenocarcinoma.35

miRNAs involved in the formation of the tumor microenvironment and angiogenesis

miRNAs involved in the tumor microenvironment of lung cancer

Disordered miRNAs can affect cancer proliferation, angiogenesis, tumor metastasis, etc. by regulating the tumor microenvironment.36

miRNAs involved in tumor angiogenesis

Neovascularization ensures that the required nutrients and oxygen are brought to the tumor tissue and is a backup force in the progression of the tumor. Many studies have demonstrated that miRNAs have a regulatory role in tumor angiogenesis.37 Vascular endothelial growth factor (VEGF) is more important in this process because it directly stimulates vascular endothelial cells to promote neovascularization and increase microvascular permeability. It has also been found that miR143/145 in lung adenocarcinoma significantly promotes tumor angiogenesis by stimulating the proliferation of endothelial cells, mainly through the targeting of Camk1d (an inhibitory kinase) by miR145.38 There is also a lung cancer-derived exosome miR23a that increases angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1 under hypoxic conditions.39 Studies have shown that in NSCLC, miR1 can reduce VEGF-induced mouse lung endothelial cell proliferation. The miRNA also reduces de novo DNA synthesis by targeting the thrombopoietin receptor in lung endothelial cells and by activating extracellular signal-regulated protein kinase 1/2 in human umbilical vein endothelial cells to inhibit tumor growth and angiogenesis.40 MiR135a inhibits tumor angiogenesis by inhibiting IGF1 by decreasing the expression of angiogenesis-related factors VEGF, bFGF and IL8 in A549 cells.16 Furthermore, miR204 may attenuate angiogenesis in lung adenocarcinoma via the JAK2-STAT3 pathway.41 These studies have shown that miRNAs play various roles in tumor angiogenesis. Other miRNAs that affect tumorigenesis through the tumor microenvironment are shown in Table 2.28,42–49

Table 2

MicroRNAs that affect tumorigenesis through the tumor microenvironment

miRNAtargetTumor suppressor/oncogeneLung cancer typeRef
miR105Mcl1oncogeneNSCLCJin et al.42
miR505MAP3K3suppressorNSCLCTang et al.28
miR3127-5pFZD4suppressorNSCLCYang et al.43
miR182MetsuppressorNSCLCLi et al.44
miR598DERL1suppressorNSCLCYang et al.45
miR145/miR497MTDHsuppressorNSCLCYin et al.46
miR103aPTENoncogeneNSCLC/SCLCHsu et al.47
miR1246CXCR4suppressorNSCLC/SCLCXu et al.48
miR138SOX4/p53suppressorNSCLCLi et al.49

miRNAs involved in tumor invasion and metastasis

Invasion and metastasis are complicated processed that are both important causes of the poor prognosis of cancer. A large number of studies have found that miRNA expression profiles are closely related to the invasion and metastasis of lung cancer. Exosomal-mediated miR193a-3p, miR210-3p and miR5100 metastasis can promote lung cancer cell invasion by activating STAT3 signaling-induced EMT.50 Overexpressed miR302b-3p inhibits the proliferation, migration and invasion of NSCLC cells by the direct targeting of GCNT3.5 In NSCLC, miR409 inhibits the growth, proliferation and migration of cancer cells by directly targeting SPIN1.52 MiR-520a3p inhibits proliferation, migration and invasion of NSCLC via the PI3K/AKT/mTOR signaling pathway.53 A summary of the miRNAs involved in tumor invasion and metastasis are shown in Table 3.22,54–79

Table 3

MicroRNAs involved in tumor invasion and metastasis

miRNAtargetsTumor suppressor/oncogeneLung cancer typeRef
miR210LOXL4oncogenelung adenocarcinomaXie et al.54
miR342-3pAGR2suppressorNSCLCXue et al.55
miR3666BPTFsuppressorLung adenocarcinomaPan et al.56
miR146-5pclaudin12oncogeneNSCLC/SCLCSun et al.57
miR33aCAND1suppressorNSCLC/SCLCKang et al.58
miR889KLF9oncogeneNSCLCHan et al.59
miR93-5pPTEN and RB1oncogeneNSCLCYang et al.22
miR103PDCD10suppressorNSCLCYang et al.60
miR223-5pE2F8suppressorNSCLCDou et al.61
miR449aHMGB1suppressorNSCLCWu et al.62
miR373BRF2suppressorNSCLCWang et al.63
miR214JAK1suppressorNSCLC/SCLCChen et al.64
miR101ZEB1suppressorNSCLCHan et al.65
miR204PCNA1suppressorNSCLC/SCLCLi et al.66
miR758HMGB3suppressorNSCLCZhou et al.67
miR497-5pSOX5suppressorNSCLCLi et al.68
miR1246GSK3βoncogeneNSCLCYang et al.69
miR362Sema3AoncogeneNSCLCLuo et al.70
miR128-3pDrosha and DiceroncogeneNSCLCFrixa et al.71
miR320a-3pPI3K/Akt pathwaysuppressorNSCLCZhao et al.72
miR875-5pSATB2oncogeneNSCLCWang et al.73
miR26a-5pITGβ8oncogeneNSCLC, SCLCSong et al.74
miR320ap100suppressorNSCLC, SCLCXing et al.75
miR145-3pPDK1suppressorNSCLCChen et al.76
miR212USP9XsuppressorNSCLCChen et al.77
miR24-3pSOX7oncogeneNSCLC, SCLCYan et al.78
miR150SIRT2/JMJD2A pathwayoncogeneNSCLCJiang et al.79

The role of miRNAs in the diagnosis of lung cancer

The lack of effective means of early diagnosis is the main cause of the high mortality rate of lung cancer. As such, miRNAs are often dysregulated in lung cancer and form a specific expression spectrum, which is conducive to the diagnosis of lung cancer. In a meta-analysis, the authors claimed that they could determine if a person has lung cancer based on whether 11 miRNAs, including miR210, miR21, miR155, were contained in a sputum specimen (1,009 NSCLC patients and 1,006 controls).80 It has also been found that the combination of miR205-5p and miR210-3p may be useful in the diagnosis of early stage lung cancer.81 Relevant studies found that by analyzing the serum of lung cancer patients that the expression of miR661, miR441 and miR181B-5 was significantly increased compared with healthy controls. These results indicated that miRNAs can be used as serum markers for the diagnosis of lung cancer. Overall, the efficacy of a combined imaging approach for the early diagnosis of lung cancer was significantly increased.82,83

The role of miRNAs in the treatment of lung cancer

Chemotherapy, radiotherapy, targeted therapy and ICI therapy are widely used for lung cancer treatment and different miRNAs are involved in the sensitivity and drug resistance thereof.

Chemotherapy

Platinum drugs, such as cisplatin and carboplatin, are commonly used in lung cancer chemotherapy regimens; however, the resistance of NSCLC cells to platinum-based drugs is a common cause of poor efficacy. Therefore, miRNAs are associated with chemotherapy sensitivity and drug resistance. The sensitivity of cisplatin in miR155 overexpressing NSCLC cell lines is reduced.84 Furthermore, in NSCLC, the up-regulation of miR128-3p may over-activate Wnt/β-catenin and TGFβ signaling and confer resistance to chemotherapy-resistant metastasis.85 Some studies have also found that miR96-reduced cisplatin-induced NSCLC cell apoptosis is caused by down-regulating SAMD9 expression.86 Other miRNAs that are associated with chemosensitivity or resistance to lung cancer are shown in Table 4.85,87–97

Table 4

MicroRNAs associated with chemosensitivity or resistance to lung cancer

miRNAUp/downTarget/pathwayMedicineRef.
Chemo-sensitive
miR9UPeIF5A2CisplatinCai et al.85
miR539UPDCLK1cisplatinDeng et al.88
miR202UPRas/MAPK PathwaycisplatinSun et al.90
miR155UPmiR155/TP53 feedback loopCisplatinVan Roosbroeck et al.92
miR106b-5pUPPKD2CisplatinYu et al.94
miR140UPSIRT1/ROS/JNKCisplatinLin et al.96
Chemo-resistant
miR130bUPPTENcisplatinZhang et al.87
miR181bDownBcl2cisplatinLiu et al.89
miR221UPPTENcisplatinWang et al.91
miR133bDownGSTP1cisplatinLin et al.93
miR144-3pUPNrf2cisplatinYin et al.95
miR324-5pUPFBXO11cisplatinBa et al.97

Radiotherapy

Radiotherapy is a treatment that uses radioactive rays to destroy cancer cells and is suitable for selected NSCLC and SCLC patients. However, the efficacy of radiotherapy is limited and some patients are prone to relapse, which may be due to radiation resistance in their cancer cells. Studies have shown that cell radio-sensitivity is associated with apoptosis as well as cell cycle and DNA damage. Therefore, it is particularly important to find the cause and markers that affect radiotherapy resistance. Studies have shown that, in vitro, miR155 reduces the radiotherapy sensitivity of lung cancer by inhibiting FOXO3A and TP53INP1. By contrast, inhibiting the expression of miR155 can improve the radiotherapy effect.98 Shin et al.99 studied the human lung adenocarcinoma cell line A549 and found that the expression level of 8 miRNAs changed after 20 Gy and 40 Gy-exposure, while that of 10 miRNAs changed only after 40 Gy-exposure. Studies have found that the down-regulation of miR18a expression can increase the sensitivity of NSCLC cells to radiotherapy.100 Other miRNAs that associated with sensitivity or resistance to lung cancer radiotherapy are shown in Table 5.101–108

Table 5

MicroRNAs associated with sensitivity or resistance to lung cancer radiotherapy

miRNAUp/downTarget/pathwayRef.
Radio-sensitive
miR373UpTIMP2Guo et al.101
miR18a-5pUpATM and HIF1αChen et al.103
miR200aUpHGF/c-Met pathwayJiang and Du et al.104,105
miR144-5pUpATF2Song et al.107
miR99aUpATF2
mTOR		Yin et al.108
Radio-resistant
miR198downHGF/c-MET pathwayZhu et al.102
miR21UPHIF1αJiang et al.104
miR1323downPRKDCLi et al.106

Molecular targeted therapy

Many studies have reported the role of various miRNA expressions in targeted therapies. Tyrosine kinase inhibitor (TKI) is a small molecule that targets the intracellular tyrosine signaling pathway. EGFR is a glycoprotein receptor consisting of 1,186 amino acid residues with a molecular weight of 170kD. After activation, EGFR can lead to intracellular tyrosine kinase activation and phosphorylation through copolymerization to activate downstream RAS-Raf-MAPK, PI3K-Akt, and JAK/STAT pathways. This process can thereby mediate tumor cell proliferation, angiogenesis, and apoptosis inhibition. Interestingly, TKIs such as gefitinib and erlotinib are often used to treat EGFR-sensitive mutant lung cancer patients. The miRNA, miR483-3p, reverses EMT and inhibits migration, invasion and metastasis of gefitinib-resistant lung cancer cells.109 This indicates that the overexpression of Mir483-3p can effectively improve the sensitivity of gafitinib-resistant lung cancer cells to gafitinib. Other miRNAs that are associated with molecular targeted therapy for lung cancer are shown in Table 6.109–114

Table 6

MicroRNAs associated with molecular targeted therapy for lung cancer

miRNAUp/downTarget/pathwayMedicineRef.
Target- sensitive
miR135aUPRAC1GefitinibZhang et al.110
miR200cUPPI3K/Akt pathwayGefitinibZhou et al.112
Target-resistant
miR181aUPGAS7GefitinibPing et al.111
miR873UPGLI1GefitinibJin et al.113
miR138DownHOXA4GefitinibTang et al.114
miR483-3pUPintegrin β3/FAK/Erk pathwayGefitinibYue et al.109

Immunotherapy

There are programmed death-1 (PD-1) proteins in the membrane of T-cells, which, if bound with the programmed death-ligand 1 (PD-L1) on tumor cells, can be redirected to kill these tumor cells. While this theory exists, little research has been published in this field. The up-regulation of miR140 in NSCLC directly inhibits the PD-L1 and the PD-L1/cyclin E pathway to inhibit cell proliferation. These results suggest that the miR140/PD-L1/cyclin E pathway may be a potential therapeutic target for the inhibition of NSCLC cell proliferation.115

The role of miRNAs in the prognosis of lung cancer

In a study of the prognostic role of circulating miRNAs in early NSCLC, five miRNAs (miR26a-5p, miR126-3p, miR130b-3p, miR205-5p and miR21-5p) were found to be significantly associated with disease-free survival (DFS) in SCC after surgical operation. Furthermore, four miRNAs (miR130b-3p, miR26a-5p, miR126-3p and miR205-5p) were found to be significantly correlated with overall survival. In adenocarcinoma, miR222-3p, miR22-3p and miR93-5p were significantly associated with DFS,116 and other miRNAs are thought to be involved in the prognosis of lung cancer. The 5-year survival rate of patients with low expression of miR455-3p in SCLC is significantly shorter than that of patients with high expression of miR455-3p.117 High expression of miR421 is associated with positive lymph node metastasis and advanced TNM staging, and has been shown to be an independent prognostic factor for NSCLC.118 Serum miR150 predicts the prognosis of early (stage I–II) NSCLC and can promote tumor cell proliferation by targeting the tumor suppressor gene SRCIN1.119

Future directions

Studies have shown that the abnormal expression of miRNAs can be detected in many types of tumors and that miRNAs play an important role in tumorigenesis. A large number of studies have reported on the relationship between miRNAs and lung cancer and have shown that miRNAs may bring certain benefits to the early diagnosis, treatment and prognosis of lung cancer. In fact, miRNAs may be a target for drug development, and can directly participate in the proliferation, apoptosis, metabolism, invasion and metastasis of lung cancer cells or indirectly enhance the sensitivity of chemotherapy, radiotherapy, targeted therapy or immunotherapy. However, due to the large number of miRNAs and the complexity and diverse regulatory pathways of lung cancers, there are still many questions to be answered.

As of now, experts have extensively investigated the relationship between microRNAs and lung cancer, but are still looking for miRNAs that can be stably expressed in the human body and that can be helpful in the diagnosis and treatment of tumors. We expect more work to participate in studying the relationship between microRNAs and lung cancer, which is expected to bring benefits to human health in the future.

Conclusions

Although there are a large number of studies on the relationship between miRNAs and lung cancer, miRNAs have not been applied to the clinical diagnosis and treatment of lung cancer. There may be a number of issues that need to be considered before a miRNA can be used in a clinical setting. For example, the safety of miRNA in the application process must be evaluated, in addition to whether a miRNA has high sensitivity and specificity for different individuals. Furthermore, it must be examined whether a miRNA is suitable for all patients and can be continuously and stably expressed in vivo. Nevertheless, the role of miRNAs in lung cancer research has attracted many attentions and will continue to provide insights into this disease as more mechanisms are revealed.

Abbreviations

SCLC: 

small cell lung cancer

NSCLC: 

non-small cell lung cancer

SCC: 

squamous cell carcinoma

miRNAs: 

microRNAs

LDHA: 

lactate dehydrogenase a

PDK4: 

pyruvate dehydrogenase kinase 4

EGFR: 

epidermal growth factor receptor

VEGF: 

vascular endothelial growth factor

TKI: 

tyrosine kinase inhibitor

PD-L1: 

programmed death-ligand 1

Declarations

Acknowledgement

None.

Funding

This work was supported by the Excellent-Surpass-Climb Disciplines Project of The Second Xiangya Hospital of Central South University; the Scientific Research Project of Hunan Provincial Health Commission, (No. 202103020704) and the National Key Clinical Specialty Construction Projects of China.

Conflict of interest

The authors declare that there is no conflict of interest.

Authors’ contributions

Conceptualization (YHW, DT), methodology (DT, ZRZ), writing of the original draft (YHW, DT, KX), writing, review and editing of the manuscript (YHW, KX, LP, ZRZ). All authors have made an intellectual contribution to the manuscript and approved the submission.

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