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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Alpha-fetoprotein (AFP) is considered as a diagnostic and prognostic tumorous marker for HCC, and up to 70% of HCC patients showed elevated serum levels of AFP. In the past two decades, evidences have shown that AFP not only is a tumorous biomarker for diagnosing HCC, but also plays a very complicated role in regulating proliferation, apoptosis, and autophagy and inhibiting the immune response of cells. Because AFP is significantly elevated during hepatocarcinogenesis, the role of AFP in the development of HCC is a scientific problem worthy of further exploration. In this review, we reviewed the effects of AFP on hepatocyte malignant transformation and the underlying mechanisms involved in the progression of HCC.

Abnormalities in the Wnt/β-catenin pathway promote the development of hepatocellular carcinoma (HCC). Mutations in CTNNB1, which encodes β-catenin, are frequently found in clinical HCC samples, as are loss-of-function mutations in signaling pathway regulators such as axis inhibition protein 1 (Axin1) and adenomatous polyposis coli (APC). The activation of the Wnt/β-catenin pathway synergizes with other oncogenic signal molecules such as c-Met or glypican-3, contributing to HCC development. Furthermore, Wnt/β-catenin pathway activation in the tumour microenvironment (TME) leads to cold tumour and resistance to immunotherapy. In this review, we discuss two models of Wnt/β-catenin signaling activation, role of Wnt/β-catenin signaling pathway in the development of HCC, the association between Wnt/β-catenin pathway and tumour angiogenesis, metastasis, and immune escape in the TME, and the targeting of this signaling pathway for HCC treatment.

Background Recent evidences indicated that some local anaesthetic agents played a role in inhibiting the proliferation of cancer cells; Whether ropivacaine is able to promote apoptosis of hepatocellular carcinoma (HCC) cells is still unclear. The aim of this study was to investigate the effect of ropivacaine on the apoptosis of HCC cells. Methods In the present study, we treated the HCC cell lines, Bel7402 and HLE with ropivacaine. MTT, DAPI stain, trypan blue exclusion dye assay, flow cytometry, electron microscopy, computational simulation, laser confocal microscope, Western blotting, and enzyme activity analysis of caspase-3 were applied to detect the growth and apoptosis of HCC cells and to explore the role mechanism of ropivacaine. Results Ropivacaine was able to inhibit proliferation and promote apoptosis of HCC cells in a dose- and time-dependent manner. Ropivacaine also has a trait to inhibit the migration of HCC cells; ropivacaine damaged the mitochondria of HCC cells. The results also indicated that ropivacaine was able to interact with caspase-3, promote cytoplasmic caspase-3 migration into the nucleus, stimulate cleavage of caspase-3 and PARP-1, caspase-9 proteins, inhibit the expression of Bcl-2, promote expression of Apaf-1 and mitochondria release cytochrome C, and activate the activity of caspase-3. Conclusions Ropivacaine has a novel role in promoting apoptosis of HCC cells; The role mechanism of ropivacaine maybe involve in damaging the function of mitochondria and activating the caspase-3 signalling pathway in HCC cells. Our findings provide novel insights into the local anaesthetic agents in the therapy of HCC patients.

Alpha-fetoprotein (AFP) has been recognized as a key regulator of cell proliferation in hepatocellular carcinoma (HCC). However, whether AFP functions in cancer cell autophagy remains unknown. This study investigated the effects of AFP on autophagy in HCC cells. The role of AFP was studied in two HCC cell lines, PLC/PRF/5 and HLE. Cell autophagy, apoptosis, proliferation, migration and invasion were analysed with Western blotting, co-immunoprecipitation (CoIP), immunofluorescence, animal models, MTT assays, flow cytometry (FCM), Cell Counting Kit (CCK)-8, and scratch and transwell assays. In PLC/PRF/5 cells, AFP interacted with PTEN and activated PI3K/Akt/mTOR signalling. In HLE cells, overexpressed AFP similarly interacted with PTEN, leading to PI3K/Akt/mTOR activation and reduced cell autophagy. When AFP was silenced in PLC/PRF/5 cells, cell proliferation, tumour growth, migration and invasion were inhibited, and the numbers of S-phase and apoptotic cells were increased. In contrast, AFP overexpression in HLE cells enhanced cell proliferation, migration and invasion and reduced apoptosis. AFP-dependent autophagy, proliferation, migration and apoptosis were inhibited by rapamycin. In summary, AFP plays critical roles in the inhibition of autophagy and apoptosis in HCC cells and promotes proliferation, migration and invasion. The role of AFP in autophagy inhibition in HCC cells may involve the activation of PI3K/Akt/mTOR signalling.

Cryo-electron microscopy (cryo-EM) visualizes the atomic structure of macromolecules that are embedded in vitrified thin ice at their close-to-native state. However, the homogeneity of ice thickness, a key factor to ensure high image quality, is poorly controlled during specimen preparation and has become one of the main challenges for high-resolution cryo-EM. Here we found that the uniformity of thin ice relies on the surface flatness of the supporting film, and developed a method to use ultraflat graphene (UFG) as the support for cryo-EM specimen preparation to achieve better control of vitreous ice thickness. We show that the uniform thin ice on UFG improves the image quality of vitrified specimens. Using such a method we successfully determined the three-dimensional structures of hemoglobin (64 kDa), α-fetoprotein (67 kDa) with no symmetry, and streptavidin (52 kDa) at a resolution of 3.5 Å, 2.6 Å and 2.2 Å, respectively. Furthermore, our results demonstrate the potential of UFG for the fields of cryo-electron tomography and structure-based drug discovery. This paper shows that the uniformity of vitreous ice thickness relies on the surface flatness of the supporting film, and presents a method to use ultraflat graphene as the support for cryo-EM specimen preparation.

A high level of serum alpha fetoprotein (AFP) is positively associated with human hepatocellular carcinoma (HCC) carcinogenesis and metastasis; however, the function of AFP in HCC metastasis is unknown. This study has explored the effects of AFP on regulating metastatic and invasive capacity of human HCC cells. Forty‐seven clinical patients' liver samples were collected and diagnosed; HCC cells line, Bel 7402 cells (AFP‐producing) and liver cancer cell line cells (non‐AFP‐producing) were selected to analyse the role of AFP in the metastasis of HCC cells. The results indicated that high serum concentration of AFP was positively correlated with HCC intrahepatic, lymph nodes and lung metastasis. Repressed expression of AFP significantly inhibited the capability of migration and invasion of Bel 7402 cells, expression of keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), matrix metalloproteinase 2/9 (MMP2/9) and CXC chemokine receptor 4 (CXCR4) were also down‐regulated in Bel 7402 cells; migration and invasion, expression of K19, EpCAM, MMP2/9 and CXCR4 were significantly enhanced when HLE cells were transfected with AFP‐expressed vector. The results demonstrated that AFP plays a critical role in promoting metastasis of HCC; AFP promoted HCC cell invasion and metastasis via up‐regulating expression of metastasis‐related proteins. Thus, AFP may be used as a novel therapeutic target for treating HCC patients.

Alpha-fetoprotein(AFP) is a cancer biomarker for the diagnosis of hepatocellular carcinoma(HCC); however, its role in macrophage polarization and phagocytosis remains unclear. In the present study, we explored the correlation between AFP regulation of macrophage function and the possible regulatory mechanisms. Human mononuclear leukemia cells (THP-1) and monocytes from healthy donors were used to analyze the effect of AFP on the macrophages’ phenotype and phagocytosis. THP-1 cells and healthy human donor-derived monocytes were polarized into M0 macrophages induced by phorbol ester (PMA), and M0 macrophages were polarized into M1 macrophages induced by lipopolysaccharide(LPS) and interferon-γ(IFN-γ). Interleukin-4(IL-4) and interleukin-13(IL-13) were used to induce M0 macrophage polarization into M2 macrophages. Tumor-derived AFP(tAFP) stimulated M0 macrophage polarization into M2 macrophages and inhibited M1 macrophages to phagocytize HCC cells. The role of AFP in promoting macrophage polarization into M2 macrophages and inhibiting the M1 macrophages to phagocytize HCC cells may be involved in activating the PI3K/Akt signaling pathway. AFP could also enhanced the migration ability of macrophages and inhibited the apoptosis of HCC cells when co-cultured with M1-like macrophages. AFP is a pivotal cytokine that inhibits macrophages to phagocytize HCC cells.

Alpha-fetoprotein (AFP) has the biological function of promoting the malignant behaviors of liver cancer cells, but how it regulates drug resistance in cancer cells is still unclear. This study explore the effect of AFP on multidrug resistance (MDR) in cancers and its potential molecular mechanisms. RNA interference vector for AFP was constructed and transduced into the human liver cancer cell line Bel 7402 (high AFP expression). However, the human cervical cancer cell line HeLa (without AFP expression) was transduced with a overexpressing AFP vector. When these cancer cells were treated with doxorubicin (ADM) and 5-fluorouracil (5-FU), cell survival rate was determined by MTT, apoptosis by TUNEL, and colony formation by colony formation assay. The cancer cells were treated with the PI3K/Akt pathway inhibitor LY294002, and the expression of drug resistance-related proteins MDR1, MRP1, BCRP, Livin, cIAP1, XIAP, Akt, p-Akt, p65, and p-p65 was detected by Western blotting. Bioinformatics analysis of the correlation between AFP regulation and intracellular signaling pathways was performed. The expression and localization of p65 were observed by immunofluorescence staining. Silencing AFP could increase the sensitivity of Bel7402 cells to ADM and 5-FU, whereas AFP overexpression caused resistance to ADM and 5-FU in HeLa cells. AFP was positively correlated with the PI3K/Akt/NF-κB signaling pathway, and there was a significant difference in the correlation between p65 and drug resistance genes. AFP regulates the expression of drug resistance-related genes by activating the PI3K/Akt/NF-κB signaling pathway. AFP plays a pivotal role in MDR of cancer cells, the mechanism may be involved in activating the PI3K/Akt/NF-κB signaling pathway.

Deubiquitinating enzymes (DUBs) are a class of crucial peptidyl hydrolases within the ubiquitin system, playing a significant role in reversing and strictly regulating ubiquitination, which is essential for various biological processes such as protein stability and cellular signal transduction. Ubiquitin-specific protease 39 (USP39) is an important member of the DUBs family. Recent studies have revealed that USP39 is involved in the regulation of multiple cellular activities including cell proliferation, migration, invasion, apoptosis, and DNA damage repair. USP39 also plays a significant role in the development and progression of various cancers. It is believed that USP39 is a unique enzyme that controls the ubiquitin process and is closely associated with the occurrence and progression of many cancers, including hepatocellular, lung, gastric, breast, and ovarian cancer. This review summarizes the structural and functional aspects of USP39 and its research advancements in tumors, investigates the key molecular mechanisms related to USP39, and provides references for tumor diagnosis and treatment.

Hepatocellular carcinoma (HCC) remains a global health challenge owing to its widespread incidence and high mortality. HCC has a specific immune tolerance function because of its unique physiological structure, which limits the efficacy of chemotherapy, radiotherapy, and molecular targeting. In recent years, new immune approaches, including adoptive cell therapy, tumor vaccines, and oncolytic virus therapy, have shown great potential. As the efficacy of immunotherapy mainly depends on the spatial heterogeneity of the tumor immune microenvironment, it is necessary to elucidate the crosstalk between the composition of the liver cancer immune environment, from which potential therapeutic targets can be selected to provide more appropriate individualized treatment programs. The role of spatial heterogeneity of immune cells in the microenvironment of HCC in the progression and influence of immunotherapy on improving the treatment and prognosis of HCC were comprehensively analyzed, providing new inspiration for the subsequent clinical treatment of liver cancer.