REVIEW ARTICLE Year : 2022  |  Volume : 18  |  Issue : 7  |  Page : 1860-1866

Useful genes for predicting the efficacy of transarterial chemoembolization in hepatocellular carcinoma

Yuan Guo1, Hongtao Hu1, Shijun Xu2, Weili Xia1, Hailiang Li1
1 Department of Minimal Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
2 Department of Radiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China

Date of Submission15-Jul-2022Date of Decision13-Oct-2022Date of Acceptance29-Oct-2022Date of Web Publication11-Jan-2023

Correspondence Address:
Hailiang Li
Department of Minimal Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou - 450 008
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jcrt.jcrt_1479_22

Transarterial chemoembolization (TACE) is generally used to treat patients with hepatocellular carcinoma (HCC), a common and deadly cancer; however, its efficacy varies according to factors such as tumor volume, stage, serum alpha-fetoprotein level, and chosen feeding artery. In addition, gene-related factors have been recently suggested to be involved in the regulation and prediction of TACE outcomes. Accordingly, genes could serve as effective biomarkers to select patients who can benefit from TACE. These gene-related factors can activate signaling pathways affecting cancer cell survival while regulating the epithelial–mesenchymal transition, angiogenesis, and the tumor microenvironment, all directly associated with tumor progression, thereby affecting TACE efficacy. Moreover, this disordered gene expression is associated with poor prognosis in patients with HCC, including TACE resistance, postoperative recurrence, and metastasis. To identify the exact relationship between various genes and TACE efficacy, this review summarizes the involvement of protein-coding and non-coding genes and single nucleotide polymorphisms in TACE efficacy for predicting the efficacy of TACE; the present findings may help improve the efficacy of TACE in clinical settings.

Keywords: Biomarker, genes, hepatocellular carcinoma, prognosis, transarterial chemoembolization

How to cite this article:
Guo Y, Hu H, Xu S, Xia W, Li H. Useful genes for predicting the efficacy of transarterial chemoembolization in hepatocellular carcinoma. J Can Res Ther 2022;18:1860-6
How to cite this URL:
Guo Y, Hu H, Xu S, Xia W, Li H. Useful genes for predicting the efficacy of transarterial chemoembolization in hepatocellular carcinoma. J Can Res Ther [serial online] 2022 [cited 2023 Jan 13];18:1860-6. Available from: https://www.cancerjournal.net/text.asp?2022/18/7/1860/367463  > Introduction 

Liver cancer is the sixth most common cancer and the third leading cause of cancer-related death worldwide.[1] Hepatocellular carcinoma (HCC) represents approximately 90% of all primary liver cancer cases; its associated morbidity and mortality have been recently increasing.[2] Current treatment methods include curative liver resection, ablation, liver transplantation, transarterial chemoembolization (TACE), and systemic treatments.[3]

TACE is a localized treatment widely used in patients with unresectable HCC and the basic treatment for intermediate-stage HCC.[4] TACE can significantly control tumor progression, be combined with other treatments, and prolong the overall survival of patients with intermediate-stage HCC.[5] However, its curative effects greatly vary among patients.[6]

TACE efficacy is related to various factors. Given the lack of an effective method to predict TACE efficacy in clinical practice, accurate TACE application remains a problem. In general, appropriate biomarkers can be accurately and repeatedly measured to serve as quantitative indicators of health and disease, effectively improving patient prognosis.[7] Because numerous genes are associated with TACE efficacy, they could be potential biomarkers for predicting TACE efficacy.

To inform the use of genes as biomarkers in predicting the efficacy of TACE in the clinic and improve patient prognosis, this review summarizes the existing literature on coding and non-coding genes and single nucleotide polymorphisms (SNPs) related to TACE efficacy in the treatment of liver cancer.

 > Protein-coding Genes and TACE Efficacy Prediction 

Protein-coding genes are DNA sequences that can produce protein products under appropriate conditions; these products have functions such as maintenance of tissue growth, renewal, and repair or participation in catalysis, regulation, and transport.[8] Abnormal protein expression can thus be extremely problematic. Cancer is a cumulative genetic disease caused by mutations in multiple genes that regulate cell growth.[9] As numerous protein-coding genes participate in these functions, TACE efficacy in HCC is affected by mutations in those genes [Table 1].

Enzyme-encoding genes

Abnormal enzyme expression can affect TACE efficacy against HCC. Aerobic glycolysis in HCC regulates numerous properties of cancer cells, including proliferation, immune escape, angiogenesis, invasion, metastasis, and drug resistance.[10] A study investigating the postoperative efficacy of TACE in patients with HCC reported high expression of a splice variant of the glycolytic gene pyruvate kinase (PKM2) in TACE-resistant patients, associated with poor overall survival (OS).[11] Conversely, PKM2 knockdown in liver cancer cell lines decreases proliferation and invasion but increases sensitivity to adriamycin and cisplatin, thereby reversing TACE resistance, similar to treatment with the PKM2 pharmacological inhibitor shikonin.[12] Enzymes such as PKM2 that affect multiple properties of HCC include peptide arginine deiminase IV (PADI4) and chromobox homolog 4 (CBX4). PADI4 is a histone-modifying enzyme that can convert arginine into citrulline. The increased PADI4 expression after TACE was related to a multidrug resistance phenotype and increased autophagy in liver cancer cells, leading to TACE resistance and poor prognosis.[13] On the other hand, a retrospective study reported that CBX4, a small ubiquitin-related modification of E3 ligase, was highly expressed in patients with HCC, who had prolonged OS after TACE. Further in vitro experiments confirmed higher sensitivity to doxorubicin in liver cancer cell lines with high CBX4 expression levels.[14]

The proteins deacetylase SIRT7 and N-acetylglucosamine phosphotransferase 1 (DPAGT1) affect TACE efficacy against HCC via drug resistance. SIRT7, a member of the silent information regulatory protein (Sir2) family, is involved in cell cycle regulation.[15]SIRT7 was upregulated in clinical HCC tissue samples and associated with decreased patient survival. Both in vivo and in vitro experiments demonstrated that the inhibition of SIRT7 expression enhanced the sensitivity of liver cancer cells to adriamycin and increased cell apoptosis, probably through the p53-dependent cell death pathway.[16]DPAGT1 is involved in glycoprotein biosynthesis, thereby mediating the N-glycosylation of many cancer-related proteins.[17] Furthermore, DPAGT1 is regulated by miR-325e3p. In patients with hepatitis B virus-related HCC undergoing TACE, high levels of DPAGT1 expression and low levels of miR-325e3p expression in tumors were associated with poor chemotherapy responses.[18]

Cyclooxygenase 2 (COX-2) and Cezanne (OTUD7B) affect TACE efficacy in HCC treatments due to their influence on the epithelial–mesenchymal transition (EMT) and the invasion and metastatic abilities of cancer cells. TACE produces a hypoxic environment that can induce the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and COX-2; in turn, both can regulate EMT and the formation of new blood vessels, thereby increasing the invasive and metastatic abilities of cancer cells, leading to poor prognosis.[19] High levels of Cezanne, a deubiquitinase of the OTU domain-containing protein family, were associated with poor OS in patients with non-small cell lung cancer.[20] However, in patients with HCC undergoing TACE, Cezanne expression was associated with tumor size, vascular invasion, satellite nodules, and the inhibition of cell invasion through the NF-κB-mediated EMT pathway and, therefore, with prolonged patient survival.[21]

Telomerase reverse transcriptase (TERT) is a catalytic subunit of the enzyme telomerase which plays an important role in cancer development as it promotes chromosome stability by maintaining telomere length, thereby avoiding cell senescence.[22] High TERT expression levels were associated with a significantly shorter time to progression in patients with HCC after TACE.[23]

Genes encoding receptors

Altered receptor-ligand activity involving C-X-C chemokine receptor type 7 (CXCR7), insulin-like growth factor 2 receptor (IGF2R), and the tyrosine kinase receptor encoded by the proto-oncogene MET (c-Met) can affect tumor growth, invasion, metastasis, apoptosis, angiogenesis, and the tumor microenvironment.[24] Recent studies have reported that altered receptor activity affected TACE efficacy in HCC treatments. CXCR7 is a receptor of C-X-C motif chemokine ligand 12 (CXCL12), also known as stromal cell-derived factor-1 (SDF-1).[25] In patients with HCC undergoing TACE, CXCR7 knockdown reduced the expression of vascular endothelial growth factor A (VEGF) and downregulated extracellular matrix proteases (MMPs) contributing to tumor cell invasion, thus reducing tumor cell invasion and improving TACE efficacy.[22] Unlike CXCR7, IGF2R is a tumor suppressor gene. Insulin-like growth factor-II (IGF-II) affects the growth and survival of cells by activating IGF2R,[26] whose expression was increased in preoperative patients with HCC after TACE. This was associated with a higher 5-year recurrence-free survival rate after surgery.[27]c-Met is a receptor for the ligand hepatocyte growth factor.[28] In contrast to the beneficial effect of high IGF2R expression in patients with HCC, the hypoxic environment induced by preoperative TACE increased c-Met expression, leading to TACE resistance and poor prognosis.[3]

Genes encoding transcription factors

TACE efficacy in treating HCC is affected by the transcription factor p53, which is encoded by TP53, a commonly mutated gene in human tumors.[29]TP53 mutations in HCC induce the activation of the mitogen-activated protein kinase pathway and some apoptotic pathways, resulting in TACE resistance and poor prognosis.[30] The hippo signaling pathway plays a key regulatory role in cell proliferation, apoptosis, and organ size control by inhibiting transcriptional regulator yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ) and has been investigated in association with TACE resistance.[31]YAP1 can be regulated by microRNA-590-5p to promote the proliferation of liver cancer cells, reduce cell apoptosis, and induce TACE resistance. Accordingly, YAP1 expression was significantly higher in TACE-resistant patients with HCC than in TACE-responsive patients and highly expressed in HCC cell lines resistant to doxorubicin.[32]

Other protein-coding genes

XRCC4-like factor (XLF) and transmembrane protein 47 (TMEM47) are associated with TACE resistance in HCC treatments. Some chemotherapeutics used in TACE can induce DNA damage in liver cancer cells,[33] among which DNA double-stranded breaks (DSBs) are the most cytotoxic.[34]XLF plays a key role in nonhomologous end joining (NHEJ) and is a major repair mechanism for DSBs.[35] Contrary to its beneficial repair effects in normal cells, XLF can enhance NHEJ activity in cancer cells, repairing DSBs caused by TACE and inducing drug resistance in cancer cells. After TACE treatment, patients with high XLF expression levels had a shorter OS and disease-free survival (DFS).[36]TMEM47 is involved in maintaining cell junction organization, and similarly to other TMEM family proteins involved in carcinogenesis and chemotherapy resistance which can be used as prognostic tumor biomarkers,[37]TMEM47 expression was higher in the tumors of TACE-resistant patients, whereas its inhibition increased the sensitivity of liver cancer cells to cisplatin treatment by enhancing caspase-mediated apoptosis.[38]

Interleukin 17 (IL-17), monocarboxylic acid transporter 4 (MCT4), and CD147 influence TACE efficacy in HCC treatments by affecting the migratory ability of cancer cells. Knocking down IL-17, which is highly expressed in HCC tissues, reduced mouse plasma VEGF levels, increased the expression of E-cadherin protein, and downregulated vimentin expression. Together, these effects inhibited the migration and invasion of liver cancer cells and tumor angiogenesis, improving prognosis.[39] Moreover, MCT4 is involved in the glycolytic metabolism of cancer cells, mediating lactic acid export.[40] High MCT4 expression after TACE was associated with poor DFS and OS. In vitro experiments confirmed that knocking down MCT4 reduced the phosphorylation of a cellular homolog of the murine thymoma virus akt8 oncogene (AKT), HIF-1 α expression, and the migration and invasion ability of cancer cells.[41] In a starvation environment induced after TACE in HCC, upregulated CD147 expression could increase the activity of the P13K/AKT/mTOR pathway and reduce liver cancer cell death, resulting in a poor prognosis.[42]

 > Non-coding Genes and TACE Efficacy Prediction 

Non-coding sequences include miRNAs, long ncRNAs (lncRNAs), circular RNAs (circRNAs), transfer RNA (tRNA)-derived small RNAs (tsRNAs), P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs), and pseudogenes.[43] miRNAs are tissue-specific and highly conserved, ranging between 17 and 25 nucleotides in length; they account for approximately 3% of the human genome[44],[45] and can act as both oncogenes and tumor suppressor genes, regulate the tumor microenvironment, and participate in almost every genetic pathway involved in tumor growth, invasion, apoptosis, and angiogenesis.[46],[47] They are reportedly the most closely related to TACE efficacy in HCC treatments.

Four single miRNAs (miR-93, miR-125b, miR-126, and miR-1285-3p) are associated with TACE efficacy in HCC treatments. In a clinical cohort study, the prognosis of patients with HCC and low miR-93 expression improved after TACE.[48] This may be related to miR-93 binding to the 3′-UTR of myostatin-related protein 3 (MTMR3), which enhances the self-renewal ability of liver tumor-initiating cells (T-ICs), promoting tumorigenesis, metastasis, and drug resistance.[49] miR-125b affects various signaling pathways and regulates cell proliferation, apoptosis, and differentiation.[50] In a cohort study, patients with HCC and low miR-125b expression in tumors had a significantly shorter time of recurrence after TACE. This may be attributed to the activation of the HIF1α/pAKT loop in the absence of miR-125b, leading to TACE resistance in patients with HCC.[51] Sprouty-related EVH1 domain-containing 1 (SPRED1) is a tumor suppressor, whereas miR-126 exhibits tumor-suppressive and angiogenic effects. miR-126 expression significantly increases in hypoxic HCC tissues after TACE, resulting in inhibited SPRED1 expression, increased VEGF levels and microvessel density, and TACE resistance.[45] Furthermore, low miR-1285-3p plasma expression levels were associated with poor TACE efficacy against HCC.[52]

Analyzing multiple miRNAs in tandem may help predict TACE efficacy in HCC treatments. Significant miR-10a-1, miR-23a-1, miR-24, miR-26a, miR-27a, miR-30c, miR-30e, miR-106b, miR-133b, miR-199a, miR-199-3p, and miR-200b upregulation before treatment was associated with a poor TACE efficacy for HCC. This may be related to enhanced EMT induced by TGF-β. Moreover, miR-27a and miR-130b can stimulate MDR1-mediated drug resistance in HCC cells and miR-23a can increase drug sensitivity via topoisomerase levels.[53] In addition, high expression levels of miR-200a, miR-21, miR-122, and miR-224-5p in HCC after TACE were also associated with poor OS.[54]

 > SNPs Involved in TACE Efficacy 

SNPs are DNA sequence variations at specific locations in the genome,[55] accounting for >90% of all variations in the human genome.[56] SNPs affect gene function through translational or post-translational mechanisms, such as miRNA binding, gene splicing, protein folding, and mRNA degradation.[57] The SNPs of many different genes influence TACE efficacy in HCC treatments.

SNPs of enzyme-related genes

The SNPs of metabolic enzymes and genes related to enzyme activity are correlated with TACE efficacy in HCC treatments. Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2), involved in the mitochondrial tricarboxylic acid cycle, have been linked to several human cancers.[58] Among patients with HCC undergoing TACE, those with the IDH1 SNP rs12478635 WV and VV genotypes had a higher risk of death than those with the WW genotype. Similarly, the IDH2 SNP rs11632348 VV genotype was significantly associated with an increased risk of death in patients with HCC.

Moreover, the SNPs of glutathione S-transferase omega 2 (GSTO2) were related to TACE efficacy in HCC treatments. GSTO2 is involved in numerous cell detoxification processes as well as cell signal transduction and cell apoptosis.[59] The median survival time of patients with the GSTO2 rs157077 mutant allele AG+GG was significantly shorter than that of wild-type homozygous AA carriers.[60] Alpha-ketoglutarate-dependent dioxygenase (fat-mass and obesity-associated protein, FTO) is a demethylase involved in the chemical modification of N6-methyladenosine (m6A). M6A plays a dominant role in RNA modifications in eukaryotic cells.[61] The survival time of patients with HCC carrying the FTO rs7202116 AA genotype after undergoing TACE was significantly higher than that of patients with the GG and AG genotypes. The YTH domain-containing 2 (YTHDC2) and FTO jointly participate in binding to m6A. YTHDC2 has various genetic variants. Compared to patients with YTHDC2 rs6594732 AC and CC genotypes, patients with HCC and the AA genotype have longer survival times after TACE. Similarly, the survival time of patients with HCC and the YTHDC2 rs10071816 GG genotype was longer than that of patients with the AA and GA genotypes after TACE; conversely, the median survival time of patients with the YTHDC2 rs2303718 GG genotype after TACE was significantly shorter than that of patients with the AA and GA genotypes.[62] Serine protease inhibitor clade E member 1 (SERPINE1), also known as plasminogen activator inhibitor type 1 (PAI-1), is involved in the malignant behavior of various tumors.[63] The 4G/4G genotype of SERPINE1 is defined as a guanosine insertion/deletion polymorphism at −675 bp in the promoter region. This genotype was associated with increased plasma plasminogen activator inhibitor-1 (PAI-1) levels and a shorter OS in patients with HCC after TACE.[64]

SNPs of other protein-coding genes

The circadian genes, neuronal PAS domain-containing protein 2 (NPAS2) and period circadian regulator 3 (PER3), the calcium-sensing receptor (CaSR), solute carrier family 1 member 5 (SLC1A5, also known as ASCT2), and epithelial cell adhesion molecule (EpCAM) were also associated with TACE efficacy in HCC treatments. Circadian genes regulate DNA damage response pathways and cell cycle functions by controlling the expression of downstream target genes, thus participating in tumor development and progression.[65],[66],[67]NPAS2 is among the nine core circadian genes. The NPAS2 SNP rs1053096 VV and rs2305160 WV and VV genotypes were significantly associated with poor prognosis in patients with HCC after TACE.[68]PER3 is a negative-feedback regulator gene of the circadian rhythm. The median survival time of patients with HCC with the PER3 SNP rs2640908 WW genotype was significantly shorter than that of patients with the WV and VV genotypes.[69] On the other hand, CaSR plays an important role in maintaining calcium homeostasis and functions as an oncogene or tumor suppressor in various tissues.[70] The CaSR SNP rs17251221 AG/GG genotype was associated with increased OS in patients with HCC after TACE.[71]ASCT2 plays a role in the exchange of essential amino acids.[72] Patients with HCC and the ASCT2 rs2070246 T genotype had better OS after TACE than those with the CC genotype.[73]EpCAM is a membrane protein involved in cell proliferation, differentiation, adhesion, and migration.[74] The EpCAM SNP rs1126497 variant genotypes WV and VV were associated with a poorer OS in patients with HCC and portal vein tumor thrombi after TACE.[75]

SNPs of non-coding genes

SNPs in lncRNA H19 are also associated with the risk for various cancers.[76] Patients with HCC and the H19 rs3741219 CC genotype had a longer OS after TACE than carriers of the TT genotype. Moreover, low lncRNA H19 expression significantly improved the efficacy of oxaliplatin treatment in cancer cells in vitro.[77] In contrast, patients with HCC and the miR-196a2 rs11614913 TT genotype had a longer OS after TACE than those with the CT and CC genotypes. With respect to miR-499a, the OS of patients with HCC with the miR-499a rs3746444 AA genotype was higher than that of AG and GG genotype carriers.[78]

 > Conclusions 

Our understanding of the relationship between HCC and TACE has improved. Changes in protein expression levels can alter the characteristics of cancer cells, thus reducing cell sensitivity to chemotherapy and leading to TACE resistance. The hypoxic environment caused by TACE can also induce HIF-1α, which is involved in tumor angiogenesis, cell survival, and invasion; its production is regulated by MCT4 and COX-2. Changes induced by TACE-induced hypoxia and other genetic changes can induce VEGF expression to promote angiogenesis or regulate extracellular matrix proteases and enhance EMT. These factors can increase the invasive and metastatic abilities of HCC cells after TACE and worsen patient prognosis.

Although some biomarkers and genes involved in TACE efficacy in HCC have already been identified, there are still some limitations to be addressed. Despite the similar effects of many reported genes on different types of tumors, there are some exceptions. For example, Cezanne has opposing roles in non-small cell lung cancer and HCC. Moreover, miR-126 is a tumor suppressor in various tumors but decreases TACE efficacy in HCC treatments. Such differences need to be further investigated. The accuracy, sensitivity, and specificity of research methods should also be improved to meet the requirements for clinical application. Furthermore, cancer diagnosis and prognostic monitoring using diverse approaches are required to accelerate the application of genetic biomarkers to clinical practice.

Acknowledgment

Thanks to Dr. Jun Lu for his helpful advice.

Author contributions

The manuscript has been read and approved by all of the authors. The requirements for authorship have been met, and each author believes that the manuscript represents honest work.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China [grant number 82002596], the Science and Technology Department of Henan Province [grant number 212102310162], and the Medical Science and Technology Research Project of Henan Province [grant number LHGJ20190633].

Conflicts of interest

There are no conflicts of interest.

 

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