Hepatocellular carcinoma (HCC) is often associated with pre-existing chronic liver pathologies of different origin infections of hepatitis B virus (HBV) and hepatitis C virus. Clinically, the diagnosis and therapy for HCC are very important for the prognosis of patients. However, current methods for HCC diagnosis and therapy have no an optimal accuracy due to the tumor heterogeneity and the frequent late diagnosis. This review summarizes the new advances in molecular diagnosis and therapy of HCC, based on the recent novel biomarkers and new therapeutic strategies for HCC, including alpha-fetoprotein-L3, glypican-3, heat shock protein 90, dickkopf WNT signaling pathway inhibitor 1, paraoxonase 1, highly up-regulated in liver cancer. Moreover, epigenetic regulation, signal pathway, cellular and molecular targets for the immunotherapy, tumor microenviroment and genome sequencing analysis may serve as the molecular expression signatures in clinical practice. For promising new treatment strategy of HCC, targeting molecular therapy based on the restoration of tumor suppressor genes lost and inhibition of oncogenic genes is attractive. The new clinical trials for other molecular-targeted agents, including pembrolizumab, nivolumab, tivantinib, lenvatinib, cabozantinib, and ramucirumab, are ongoing in clinic. Interestingly, anti-HBV drugs display an amazing therapy for HBV-related HCC. In future, the global determination of more biomarkers may provide new insights into the diagnosis of HCC. More importantly, the diagnostic markers should be used to trace patient’s follow-up disease progression, guiding doctors to judge and prescribe drugs for status of an illness, prognosis and other processes.
Hepatocellular carcinoma (HCC) is a serious health issue globally. The increased trends of HCC will remain until 2030[
Molecular mechanisms of malignant cells will lead to the development of successful HCC therapies. NcRNAs and epigenetic regulation have been considered as a potential non-invasive biomarkers due to their experimental and clinical versatility. Whole-genome sequencing analysis has promoted molecular profiles transduced in expression “signatures” which will help in the comprehension of liver physiopathology. HCC etiology seems to be a factor that should be included in several clinic association studies.
The development of novel and useful biomarkers can be employed as a screening strategy for early diagnosis and prognosis in these high-risk populations, since HCC presents a high mortality rate[
The present methods for diagnosis of HCC can be divided into the following major aspects: magnetic resonance imaging, abdominal ultrasonography, and contrast-enhanced computed tomography, liver biopsy, and serological test. However, the diagnostic effectiveness of above technologies is not very satisfied, particularly for the diagnosis of small lesions and early diagnosis of HCC. The abdominal ultrasound is an operator-dependent test. Liver biopsy is an invasive method not exempt of mortality risk[
As we know, cellular miRNAs released into the extracellular circulation system can be detected by serological test. Owing to circulating miRNAs relevant to HCC, miRNAs may serve as potential biomarkers. Thus, some circulating miRNAs can be considered as representative of certain pathological conditions. Moreover, circulating miRNAs possess accessibility well and high stability in the detection system, particularly for supervision of early stage, pre-symptomatic diseases in at-risk patients[
MiRNAs may be used as biomarkers for prognosis or diagnosis in HCC. Down-regulation of miR-let-7g, miR-22, miR-26, miR-29, miR-99a, miR-124, miR-139, miR-145 and miR-199b is involved in the cell’s life activities, including proliferation, apoptosis, angiogenesis, disease recurrence, disease-free survival (DFS) and poor prognosis[
Serum diagnostic markers in hepatocellular carcinoma
Biomarkers | Sensitivity (%) | Specificity (%) |
---|---|---|
AFP[ |
60.0 | 85.0 |
AFP-L3[ |
84.9 | 86.4 |
DCP[ |
80.0 | 81.0 |
AFP + AFP-L3 + DCP[ |
94.3 | 86.4 |
PON[ |
41.6 | 85.7 |
Fuc-PON1[ |
79.1 | 53.5 |
Hsp90α[ |
93.32 | 90.27 |
Hsp90α + AFP[ |
93.70 | 94.40 |
MiR-101[ |
95.5 | 90.2 |
MiR-18a[ |
86.1 | 75 |
AFP: alpha-fetoprotein; AFP-L3: lens culinaris agglutinin (LCA)-reactive AFP; DCP: C-carboxy prothrombin; PON1: paraoxonase 1; Fuc-PON1: PON1-fucosylated level protein; HSP90α: heat shock protein 90 alpha
Furthermore, it has been reported that miR-500 is highly expressed in the sera of HCC patients. While, after surgical treatment, the expression level is reduced[
Long non-coding RNAs (lncRNAs) are a subgroup of non-coding RNA transcripts greater than 200 nucleotides in length with little or no protein-coding potential. Emerging evidence indicates that lncRNAs may play important regulatory roles in the pathogenesis and progression of human cancers, including HCC. Certain lncRNAs may be used as diagnostic or prognostic markers for HCC, a serious malignancy with increasing morbidity and high mortality rates worldwide. LncRNA HOX transcript antisense intergenic RNA (Hotair) which can bind to lysine-specific demethylase 1 (LSD1) is a 2.2 kilobase ncRNA residing in the HOXC locus. Hotair serves as a scaffold of histone modification complexes including LSD1 and polycomb-repressive complex 2, leading to the development of various tumors[
Taken together, the development of lncRNA expression profiling using high-throughput technology for specific HCC biomarkers will no doubt lead to more accurate and precise clinical decision-making having the consequence of better patient care in the future. While the first miRNA (lin-4) was identified two decades ago, other ncRNAs including lncRNAs, snoRNAs, siRNAs and piRNAs have been surfaced and proved to be essential players in cancer pathogenesis[
DNA methylation affects the phenotype mainly through expression of the corresponding genes, methylation profiles could reflect the biological characteristics of HCC if “passive methylation” could be eliminated appropriately. A number of results have shown the predictive value of selected methylation events on survival[
About the traditional biomarkers, because the false negative rate of alpha-fetoprotein (AFP) is about 40% for early-stage HCC patients, 15%-30% of all the patients, even patients with advanced HCC, AFP levels remain normal[
Based on hepatocarcinogenesis, prevention of HBV infection is a key step to reduce the incidence of liver cancer. There is a renewed interest regarding the understanding of various steps of the HBV replication cycle, as well as specific virus-host cell interactions, to define new targets and develop new antiviral drugs. Basically, the HBV covalently closed circular DNA (HBV cccDNA) is pivotal for persistent HBV infection and recurrence by the end of treatment. As far as we know, the cccDNA usually organizes into a minichromosome with histone 3 and H4 proteins and other nonhistone proteins, such as HBx, HBV core protein, and host transcription factors[
HBx plays a crucial role in the various signal transduction pathways and HBV-induced hepatocarcinogenesis[
The research about a cohort of 956 HCC patients, 25% had high expression of programmed death-ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) in HCC tissues. Moreover, the study found that infiltrating CD8+ TILs (tumor-infiltrating lymphocyte) could induce PD-L1 expression
Tivantinib as the first drug was used to a phase III trial grounded in receptor overexpression analyses after disease progression on sorafenib in HCC[
Overview of clinical trial agents for hepatocellular carcinoma therapy
Agents | Developmental status | Targets | Outcomes |
---|---|---|---|
Nivolumab | Phase III | PD-1[ |
Ongoing[ |
Pembrolizumab | Phase III | PD-1[ |
Ongoing[ |
Ramucirumab | Phase III | VEGFR2[ |
Survival benefit for the subgroup with AFP ≥ 400 ng/mL[ |
Lenvatinib | Phase III | VEGFR1-3, FGFR1-4, PDGFRα, RET and KIT[ |
Non-inferior OS, improved PFS, TTP, and ORR[ |
Cabozantinib | Phase III | TIE-1, TIE-2, FLT3, c-MET, KIT, RET and VEGFR[ |
Significant improvement in OS, PFS, and ORR[ |
Tivantinib | Phase III | c-MET[ |
Improved OS and PFS[ |
HCC: hepatocellular carcinoma; OS: overall survival; ORR: objective response rate; PFS: progression-free survival; TKI: tyrosine kinase inhibitor; TTP: time to progression
Sorafenib as a molecular-targeted agent can attenuate HCC proliferation and angiogenesis by inhibiting RAF serine threonine kinase and VEGF, PDGF, Flt-3, c-Kit receptor tyrosine kinase, getting approved in Europe and North America in 2007 and in Japan on May 20, 2009. To our delight, a subanalysis of the SHARP study, such as sorafenib in combination with resection, ablation, transcatheter arterial chemoembolization or hepatic arterial infusion chemotherapy, will overtly extend the overall survival in early-, intermediate- or advanced-stage HCCs[
Although the effective diagnosis and therapies have been developed in HCC at present, it is unsatisfied to improve the patients’ survival. The challenges in the field of diagnosis and therapy for HCC are still ongoing. Therefore, developing new diagnostic approach and drugs are urgent. About gene diagnosis of HCC, high-throughput means combined with bioinformatics methods will be used to find out the root cause of HCC in large-scale sample research. Clinically, it is necessary to monitor the biomarkers in the development of HCC involving treatment and prognosis, but not only in the early stage. It is vital to develop kits for determining the replication activity of HBV (or HCV) and HBV cccDNA to evaluate the risk of HCC incidence. For HCC therapy, identifying innovative targets and combination with multiple drugs are still needed in the treatment strategy. Effective combination of antiviral therapies with anti-inflammation drugs involving inflammation factors is available to treat chronic HBV-related HCC. It is necessary to examine the sensitivity, specificity, predictive value positive, predictive value negative, and validity of any candidate biomarker in a large pool of HCC patients with or without HBV infection, furthermore, it is also important to follow up large patients with HBV or other risk factor exposure for the prediction of occurrence and postoperative recurrence of HCC using representative markers. If biomarkers are valid, it is necessary to develop kits for molecular diagnosis, monitoring the efficacy, prognosis and treatments of HCC patients.
In summary, this review lists the recent progresses in gene diagnosis and therapy for HCC. The achievements include the recent novel biomarkers and novel therapeutic strategies for HCC, such as AFP, AFP-L3, GPC3, HSP90, DKK1, PON1,
Drafted the outline of this review: Zhang XD
Drafted the manuscript: Zhang XD, Zhao M
Finalized the manuscript: Zhang XD, Zhao M
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All authors declare that there are no conflicts of interest.
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© The Author(s) 2019.