Correlation between prognostic markers and clinical parameters in hepatocellular carcinoma: Pathophysiological aspects to therapeutic targets

Table 1 Pathophysiological aspects of prognostic markers in hepatocellular carcinoma

Prognostic markers	Pathophysiological aspects in HCC	Ref.
MEX3A	Explained in Figure 1	[16]
APOB	APOB appears to play a crucial role in HCC pathophysiology by regulating lipid metabolism and influencing tumor progression	[22]
	APOB depletion causes a change in the balance of lipid metabolism that favors tumor development
AFP	AFP is an important component of the TME, which promotes the development of HCC, and several studies have shown that TME is essential to the malignant transformation of HCC	[55,31,69]
	Many individuals with HCC have elevated blood AFP expression levels, and elevated AFP levels over time are associated with an increased risk of HCC development
	AFP is an immune suppressor that can encourage malignant transformation during the development of HCC and may have a role in the MDR process in liver cancer patients
	High expression of AFP is closely associated with the onset and spread of HCC, making it a valuable biomarker for HCC
	Through PI3K/Akt signaling pathway activation, AFP can promote LCSC growth in the TME. Furthermore, AFP can promote the development of HCC by upregulating the expression of genes linked to LCSCs
	Furthermore, by interacting with macrophage receptors and causing tumor immune escape, AFP can preemptively interfere with macrophage-mediated phagocytosis of tumor cells
	Concurrently, AFP may weaken the function of DCs, CAFs, endothelial cells, mesenchymal stem cells, NK cells, and macrophages
	It may also hinder the capacity of cytotoxic T lymphocytes to eradicate tumor cells, which would aid in tumor immune evasion
	Higher AFP levels and higher VEGFR2 staining were linked to worse progression-free survival and overall survival. The sole independent predictor of progression-free survival and overall survival was AFP level
CTCs	The CTC count was a risk factor for HCC metastasis. Significant correlations were seen between the CTC count and MVI, vascular invasion, and tumor size	[39,61]
	CTCs, which are released into the circulation from both primary and metastatic lesions, offer important insights into the development and spread of cancers
	CTCs facilitate EMT, which leads to tumor metastasis. Stem-like characteristics and CTC clusters increase the likelihood of metastasis and aggression
	The characteristics of comparable primary tumors are mimicked by CTCs, which maintain their heterogeneity
	Consequently, single-cell-based analysis is crucial for learning about the biology and heterogeneity of tumors
SAMD13	The expression of SAMD13 in HCC samples was much greater than in normal liver tissue; it was also higher in initial tumors, different cancer stages and tumor grades, and the presence of nodal metastases	[41]
	Additionally, a worse prognosis was linked to higher SAMD13 expression
	The expression of SAMD13 was positively connected with B cells, neutrophils, macrophages, DC, CD8+ T cells, and CD4+ T cells
Agrin	Agrin promotes movement, oncogenic signaling, and cellular proliferation	[64,65,72]
	Through prolonged focal adhesion integrity, the extracellular matrix sensor activity of Agrin mechanistically offers oncogenic cues to govern Arp2/3-dependent ruffling, invadopodia formation, and EMT, all of which contribute to the development of liver tumors
	Agrin signaling also forms a crucial oncogenic axis through Lrp4-MuSK
	Antibodies that target Agrin have been shown to decrease tumor development and oncogenic signaling in vivo
	The liver tumor microenvironment plays a key role in promoting hepatocarcinogenesis, and Agrin, a secreted proteoglycan, is often overexpressed in HCC
	In the portal regions of the normal liver, Agrin was seen by immunohistochemistry around the bile ducts and blood arteries
	While Agrin was deposited in the neovascular basement membrane of HCCs, it was not expressed in the hepatic lobules
	While immunostaining caused Agrin to fragment, diminish, or even vanish in less differentiated regions and locations of infiltration, it was plentiful in the tumor-specific basement membrane in well-differentiated CCs
	Even more, Agrin was expressed in CC samples. Immunoblotting validated these results
	As a component of the newly created vasculature, our findings suggest that Agrin may be crucial to neoangiogenesis in human HCC
	However, Agrin may have a role in the development of tumors in CC
GPC3	Through its interaction with molecules including growth factors and Wnt signaling proteins, GPC3 contributes to the advancement of HCC	[44,67]
	Proliferation, metastasis, apoptosis, and EMT are all significant cellular processes that GPC3 influences via a variety of signaling pathways, including Wnt, IGF, YAP, and Hedgehog

HCC: Hepatocellular carcinoma; APOB: Apolipoprotein B; GPC3: Glypican-3; CTC: Circulating tumor cell; AFP: Alpha-fetoprotein; CC: Cholangiocarcinoma; VEGFR: Vascular endothelial growth factor receptor; EMT: Epithelial-mesenchymal transition; TME: Tumor microenvironment; MDR: Multidrug resistance; LCSC: Liver cancer stem cell; DC: Dendritic cells; CAF: Cancer-associated fibroblasts; NK: Natural killer; MVI: Microvascular invasion.

Table 2 Overview of prognostic markers as therapeutics strategies in hepatocellular carcinoma

Prognostic markers	Therapeutics in HCC	Ref.
MEX3A	In HCC, MEX3A could be a new regulator of the Hippo signaling pathway and a possible target for treatment	[16,54]
	A novel treatment approach for progressive and sorafenib-resistant HCC is provided by the combined data, which further clarifies the possible role and mechanism of MEX3A in HCC
	Via an antiangiogenic mechanism rather than by specifically targeting HCC cells, dovitinib selectively suppresses HCC development and metastasis
	MEX3A inhibition could enhance the efficacy of standard HCC treatments such as sorafenib, lenvatinib, or immunotherapy
	Combining MEX3A-targeting strategies with PD-L1 inhibitors could improve immune response against HCC
APOB	Not determined
AFP	According to recent research, AFP inhibition significantly suppresses the malignant tendencies of HCC cells, causing cancer cell death and preventing their invasion, metastasis, and proliferation	[55,69]
	For this reason, AFP is essential for the malignant development of HCC
	In the development, diagnosis, and management of HCC, AFP is a two-edged sword
	Assessing AFP levels in clinical practice is crucial for the early identification, diagnosis, and management of HCC
	Medical practitioners can guide clinical decision-making by tracking changes in AFP levels, which allows them to track the course of the disease and the effectiveness of treatment
	Additionally, physicians can employ AFP vaccinations to produce CD8+ T lymphocytes that are specific to AFP and destroy cancer cells
	Furthermore, AFP and immunotherapy together can increase the effectiveness of treatment
	Evidence for the negative predictive impact of increased baseline AFP raises the possibility that AFP plays a part in primary resistance to sorafenib treatment
CTCs	Moreover, CTCs are excellent choices for creating preclinical models (particularly 3D organoid cultures) for drug screening, disease modeling, genome editing, tumor immunity research, and the creation of organ-like biobanks	[61,62]
	According to recent research, CTCs are promising candidates for early diagnosis, assessing the prognosis of metastases or recurrences, and possibly serving as a possible target for therapy in patients with HCC
	In the future, it will be used as a novel indication in therapeutic settings
SAMD13	The potential function of SAMD13 as a therapeutic target and a promising biomarker for prognosis in HCC is highlighted by the features of its involvement in patients with HCC utilizing a variety of bioinformatics techniques	[51]
	While SAMD13 shows promise as a prognostic indicator, its potential as a therapeutic target in HCC requires further investigation
	Understanding the precise biological functions of SAMD13 in HCC progression and its interactions within the tumor microenvironment is essential
Agrin	Agrin is often overexpressed, has a significant role in the carcinogenic characteristics of HCC, and is a desirable target for antibody treatment	[64]
	Incorporating Agrin inhibitors with existing treatments, such as tyrosine kinase inhibitors or immunotherapies, may enhance overall therapeutic efficacy
	This combination strategy could potentially overcome resistance mechanisms and improve patient outcomes
GPC3	GPC3 knockdown by siRNA increased the suppression effects of curcumin on Wnt/β-catenin signaling	[43,66,73]
	Small molecules that interfere with GPC3-mediated signaling pathways are an appealing therapeutic strategy that may be used in HCC patients; however, as of yet no small molecules that target GPC3 have been developed or tested in HCC patients. Small-molecule GPC3 drugs may provide greater efficacy, stability, and safety for the treatment of HCC
	Further research is required to develop GPC3 targeting small molecular compounds
	Numerous clinical trials involving GPC3 are currently underway, and several novel GPC3-targeted therapeutic approaches, such as the GPC3 vaccine, anti-GPC3 immunotoxin, combined therapy with immune checkpoint blockades, and chimeric antigen receptor T or NK cells, have recently surfaced with promising outcomes
	Current research on GPC3 expression in human HCC, GPC3 regulation molecular mechanisms, and GPC3-targeting antibodies
	Furthermore, several immunotherapies that target GPC3 have been created, such as chimeric-antigen-receptor-modified cells, anti-GPC3 immunotoxins, and GPC3 vaccines
	After summarizing and evaluating the physicochemical characteristics and structure of GPC3 molecules, the authors go over their biological roles and clinical diagnostic uses before investigating GPC3-based diagnosis and therapy approaches

HCC: Hepatocellular carcinoma; APOB: Apolipoprotein B; CTC: Circulating tumor cell; AFP: Alpha-fetoprotein; GPC3: Glypican-3; 3D: Three-dimensional; NK: Natural killer.