The mechanism and experimental verification of Ixeris sonchifolia promoting apoptosis of hepatocellular carcinoma based on network pharmacology: Ixeris sonchifolia Induces Hepatocellular Carcinoma Apoptosis via the PI3K/AKT Pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ixeris sonchifolia alias Kudiezi, it was named Ixeris sonchifolia (Bunge) Hance, a synonym for Crepidiastrum sonchifolium (Bunge) Pak & Kawano in the https://www.iplant.cn/. And it was first published in J. Linn. Soc., Bot. 13: 108 (1873), which was named Ixeris sonchifolia (Maxim.) Hance in the MPNS (http://mpns.kew.org). As a widely distributed medicinal and edible wild plant, it possesses unique bitter-cold characteristics and constituents with various pharmacological activities. Its main antitumor substances, same as artemisinin and paclitaxel, are classified as terpenoids and have become research foci in recent years. However, its specific biological activity and role in antitumor treatment remain largely unclear. AIM OF THE STUDY: This study aimed to elucidate the molecular targets and potential mechanisms of hepatocellular carcinoma apoptosis induced by Ixeris sonchifolia. MATERIALS AND METHODS: We used network pharmacology methods to analyze and screen the active ingredients and possible underlying mechanisms of Ixeris sonchifolia in treating liver cancer and employed integrative time- and dose-dependent toxicity, transcriptomics, and molecular biology approaches to comprehensively verify the function of Ixeris sonchifolia extract (IsE) in human hepatoblastoma cell (HepG2) apoptosis and its potential mechanism. RESULTS: A total of 169 common targets were screened by network pharmacology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that IsE inhibited HepG2 cell activity in a time- and dose-dependent manner. Western blot analysis confirmed that IsE promoted HepG2 cell apoptosis by inhibiting the PI3K/AKT signaling pathway and that the PI3K/AKT inhibitor LY294002 also substantially enhanced IsE-induced apoptosis. The PI3K/AKT signaling pathway exhibited significant differences compared to that in the control group. CONCLUSION: Combining network pharmacology with experimental verification, IsE inhibited mitochondrial function and the PI3K/AKT pathway while inducing hepatoma cell apoptosis. IsE may have promising potential for liver cancer treatment and chemoprevention.

Immune-cell-mediated tissue engineering strategies for peripheral nerve injury and regeneration.

During the process of peripheral nerve repair, there are many complex pathological and physiological changes, including multi-cellular responses and various signaling molecules, and all these events establish a dynamic microenvironment for axon repair, regeneration, and target tissue/organ reinnervation. The immune system plays an indispensable role in the process of nerve repair and function recovery. An effective immune response not only involves innate-immune and adaptive-immune cells but also consists of chemokines and cytokines released by these immune cells. The elucidation of the orchestrated interplay of immune cells with nerve regeneration and functional restoration is meaningful for the exploration of therapeutic strategies. This review mainly enumerates the general immune cell response to peripheral nerve injury and focuses on their contributions to functional recovery. The tissue engineering-mediated strategies to regulate macrophages and T cells through physical and biochemical factors combined with scaffolds are discussed. The dynamic immune responses during peripheral nerve repair and immune-cell-mediated tissue engineering methods are presented, which provide a new insight and inspiration for immunomodulatory therapies in peripheral nerve regeneration.

Application of metal-organic frameworks-based functional composite scaffolds in tissue engineering.

With the rapid development of materials science and tissue engineering, a variety of biomaterials have been used to construct tissue engineering scaffolds. Due to the performance limitations of single materials, functional composite biomaterials have attracted great attention as tools to improve the effectiveness of biological scaffolds for tissue repair. In recent years, metal-organic frameworks (MOFs) have shown great promise for application in tissue engineering because of their high specific surface area, high porosity, high biocompatibility, appropriate environmental sensitivities and other advantages. This review introduces methods for the construction of MOFs-based functional composite scaffolds and describes the specific functions and mechanisms of MOFs in repairing damaged tissue. The latest MOFs-based functional composites and their applications in different tissues are discussed. Finally, the challenges and future prospects of using MOFs-based composites in tissue engineering are summarized. The aim of this review is to show the great potential of MOFs-based functional composite materials in the field of tissue engineering and to stimulate further innovation in this promising area.

CHB patients with rtA181T-mutated HBV infection are associated with higher risk hepatocellular carcinoma due to increases in mutation rates of tumour suppressor genes.

The HBV rtA181T mutation is associated with an increased risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to evaluate the mechanism by which rtA181T mutation increases the risk of HCC. We enrolled 470 CHB patients with rtA181T and rtA181V mutation in this study; 68 (22.15%) of the 307 patients with rtA181T mutation and 22 (13.5%) of the 163 patients with rtA181V mutation developed HCC (p < .05). The median follow-up periods were 8.148 and 8.055 years (p > .05). Serum HBV DNA and HBsAg levels in rtA181T-positive patients were similar to that in rtA181V-positive patients. However, the serum HBeAg levels in the rtA181T-positive patients were significantly higher than that in rtA181V-positive patients. In situ hybridization experiments showed that the HBV cccDNA and HBV RNA levels were significantly higher in the liver cancer tissues of patients with the rtA181T mutation compared to that in the tissues of patients with the rtA181V mutation. The percentage of anti-tumour hot-gene site mutations was significantly higher in the rtA181T-positive HCC liver tissue compared to that in the rtA181T-negative HCC liver tissue (7.65% and 4.3%, p < .05). This is the first study to use a large cohort and a follow-up of more than 5 years (average 8 years) to confirm that the rtA181T mutation increased the risk of HCC, and that it could be related to the increase in the mutation rate of hotspots of tumour suppressor genes (CTNNB1, TP53, NRAS and PIK3CA).

Bionic peptide scaffold in situ polarization and recruitment of M2 macrophages to promote peripheral nerve regeneration.

Tissue regeneration requires exogenous and endogenous signals, and there is increasing evidence that the exogenous microenvironment may play an even more dominant role in the complex process of coordinated multiple cells. The short-distance peripheral nerve showed a spontaneous regenerative phenomenon, which was initiated by the guiding role of macrophages. However, it cannot sufficiently restore long-distance nerve injury by itself. Based on this principle, we firstly constructed a proinflammatory model to prove that abnormal M2 expression reduce the guidance and repair effect of long-distance nerves. Furthermore, a bionic peptide hydrogel scaffold based on self-assembly was developed to envelop M2-derived regenerative cytokines and extracellular vesicles (EVs). The cytokines and EVs were quantified to mimic the guidance and regenerative microenvironment in a direct and mild manner. The bionic scaffold promoted M2 transformation in situ and led to proliferation and migration of Schwann cells, neuron growth and motor function recovery. Meanwhile, the peptide scaffold combined with CX3CL1 recruited more blood-derived M2 macrophages to promote long-distance nerve reconstruction. Overall, we systematically confirmed the important role of M2 in regulating and restoring the injury peripheral nerve. This bionic peptide hydrogel scaffold mimicked and remodeled the local environment for M2 transformation and recruitment, favoring long-distance peripheral nerve regeneration. It can help to explicate regulative effect of M2 may be a cause not just a consequence in nerve repair and tissue integration, which facilitating the development of pro-regenerative biomaterials.

Recent advances in recurrent hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, accounting for 75%-85% of cases. Although treatments are given to cure early-stage HCC, up to 50%-70% of individuals may experience a relapse of the illness in the liver after 5 years. Research on the fundamental treatment modalities for recurrent HCC is moving significantly further. The precise selection of individuals for therapy strategies with established survival advantages is crucial to ensuring better outcomes. These strategies aim to minimize substantial morbidity, support good life quality, and enhance survival for patients with recurrent HCC. For individuals with recurring HCC after curative treatment, no approved therapeutic regimen is currently available. A recent study presented novel approaches, like immunotherapy and antiviral medication, to improve the prognosis of patients with recurring HCC with the apparent lack of data to guide the clinical treatment. The data supporting several neoadjuvant and adjuvant therapies for patients with recurring HCC are outlined in this review. We also discuss the potential for future clinical and translational investigations.

Cannabidiol inhibits invasion and metastasis in colorectal cancer cells by reversing epithelial-mesenchymal transition through the Wnt/ß-catenin signaling pathway.

Colorectal cancer (CRC) is the leading cause of cancer deaths worldwide, wherein distant metastasis is the main reason for death. The non-psychoactive phytocannabinoid cannabidiol (CBD) effectively induces the apoptosis of CRC cells. We investigated the role of CBD in the migration and metastasis of CRC cells. CBD significantly inhibited proliferation, migration, and invasion of colon cancer cells in a dose- or time-dependent manner. CBD could also inhibit epithelial-mesenchymal transition (EMT) by upregulating epithelial markers such as E-cadherin and downregulating mesenchymal markers such as N-cadherin, Snail, Vimentin, and HIF-1α. CBD could suppress the activation of the Wnt/ß-catenin signaling pathway, inhibit the expression of ß-catenin target genes such as APC and CK1, and increase the expression of Axin1. Compared to the control group, the volume and weight of orthotopic xenograft tumors significantly decreased after the CBD treatment. The results demonstrated that CBD inhibits invasion and metastasis in CRC cells. This was the first study elucidating the underlying molecular mechanism of CBD in inhibiting EMT and metastasis via the Wnt/ß-catenin signaling pathway in CRC cells. The molecular mechanism by which CBD inhibits EMT and metastasis of CRC cells was shown to be through the Wnt/ß-catenin signaling pathway for the first time.

Customized Multifunctional Peptide Hydrogel Scaffolds for CAR-T-Cell Rapid Proliferation and Solid Tumor Immunotherapy.

CAR-T-cell therapies must be expanded to obtain a large number of effector cells quickly, and the current technology cannot address this challenge. A longer operational time would lose or alter the function and phenotype of CAR-T cells in response to therapy, and it also causes a loss in the optimal treatment time for patients. At present, lower survival time and homing efficiency reduce the antitumor effect of CAR-T in vivo. But nobody has solved these two issues in one system, which has a similar microenvironment of lymphoid organs to activate/expand cell delivery for immunotherapy. Here, we generated artificial, customized immune cell matrix scaffolds based on a self-assembling peptide to preserve and augment the cell phenotype in light of the characteristics of CAR-T. The all-in-one nanoscale matrix scaffolds reduced the processing time of CAR-T to 3 days and resulted in over a 10-fold increase compared with the traditional protocol. The cells were combined to modulate mechanotransduction and chemical signals, and the mimic matrix scaffolds showed optimal stiffness and adhesive ligand density, thereby accelerating CAR-T-cell proliferation. Meanwhile, engineering CAR-T-secreted intrinsic PD-1 blocking single-chain variable fragments (scFv) further increased cell proliferation and cytotoxicity by resisting the self and tumor microenvironment in a paracrine and autocrine manner. Local delivery of CAR-T cells from the scaffolds significantly enabled long-term retention, suppressed tumor growth, and increased infiltration of effector T cells compared with traditional CAR-T treatment. The application of bioengineering and genetic engineering approaches has led to the development of rapid culture environments that can control matrix scaffold properties for CAR-T-cell and cancer immunotherapies.

Near-infrared chemiluminescent nanoprobes for deep imaging and synergistic photothermal-nitric-oxide therapy of bacterial infection.

Bacterial infection is the leading cause of many serious inflammation diseases threatening human health. Existing theranostic options for bacterial infection are always complicated and unsatisfactory. There is an increasing interest in developing a more effective theranostic approach for the treatment of infections. Herein, we report the development of a near-infrared (NIR) chemiluminescent (CL) nanoparticles ALPBs containing luminol, AIE dye (TTDC), PCPDTBT, and nitric oxide (NO) donor (BNN6), which could achieve a deep CL imaging-guided photothermal-NO gas therapy of bacterial infection. After intravenous injection, ALPBs could be largely accumulated in the infected site and then activated by oversecreted reactive oxygen species (ROS) to produce near-infrared chemiluminescence, which could precisely track infection-induced local inflammation. Under the guidance of imaging, synergistic photothermal-NO therapy was further performed by 808 nm laser irradiation, leading to active bacterial eradication and rapid recovery of infected tissues. The utility of ALPBs provides a powerful and controllable "all-in-one" platform for combating bacterial infection.

The immune microenvironment and tissue engineering strategies for spinal cord regeneration.

Regeneration of neural tissue is limited following spinal cord injury (SCI). Successful regeneration of injured nerves requires the intrinsic regenerative capability of the neurons and a suitable microenvironment. However, the local microenvironment is damaged, including insufficient intraneural vascularization, prolonged immune responses, overactive immune responses, dysregulated bioenergetic metabolism and terminated bioelectrical conduction. Among them, the immune microenvironment formed by immune cells and cytokines plays a dual role in inflammation and regeneration. Few studies have focused on the role of the immune microenvironment in spinal cord regeneration. Here, we summarize those findings involving various immune cells (neutrophils, monocytes, microglia and T lymphocytes) after SCI. The pathological changes that occur in the local microenvironment and the function of immune cells are described. We also summarize and discuss the current strategies for treating SCI with tissue-engineered biomaterials from the perspective of the immune microenvironment.

RDIVpSGP motif of ASPP2 binds to 14-3-3 and enhances ASPP2/k18/14-3-3 ternary complex formulation to promote BRAF/MEK/ERK signal inhibited cell proliferation in hepatocellular carcinoma.

The Apoptosis Stimulating Protein of p53 2 (ASPP2) is a heterozygous insufficient tumor suppressor; however, its molecular mechanism(s) in tumor suppression is not completely understood. ASPP2 plays an essential role in cell growth, as shown by liver hepatocellular carcinoma (LIHC) RNA-seq assay using the Cancer Genome Atlas (TCGA) and High-Throughput-PCR assay using ASPP2 knockdown cells. These observations were further confirmed by in vivo and in vitro experiments. Mechanistically, N-terminus ASPP2 interacted with Keratin 18 (k18) in vivo and in vitro. Interestingly, the RDIVpSGP motif of ASPP2 associates with 14-3-3 and promotes ASPP2/k18/14-3-3 ternary-complex formation which promotes MEK/ERK signal activation by impairing 14-3-3 and BRAF association. Additionally, ASPP2-rAd injection promotes paclitaxel-suppressed tumor growth by suppressing cell proliferation in the BALB/c nude mice model. ASPP2 and k18 were preferentially downregulated in Hepatocellular Carcinoma (HCC), which predicted poor prognosis in HCC patients. Overall, these findings suggested that ASPP2 promoted BRAF/MEK/ERK signal activation by promoting the formation of an ASPP2/k18/14-3-3 ternary complex via the RDIVpSGP motif at the N terminus. Moreover, this study provides novel insights into the molecular mechanism of tumor suppression in HCC patients.

ß-Asarone Protects PC12 Cells Against Hypoxia-Induced Injury Via Negatively Regulating RPPH1/MiR-542-3p/DEDD2 Axis.

Hypoxic injury to the brain is very intricate under the control of biochemical reactions induced by various factors and mechanisms. Long non-coding RNAs (lncRNAs) have already been revealed to affect pathological processes in the nervous system of different degrees. This research aimed to investigate the mechanisms implicated in hypoxic brain injury. ß-Asarone mitigated the decrease of cell viability, superoxide dismutase activity, and mitochondrial membrane potential, as well as the increase of cell apoptosis, lactate dehydrogenase release, malondialdehyde content, and reactive oxidative species production by cobalt chloride. LncRNA ribonuclease P RNA component H1 (RPPH1) was discovered to be highly expressed in hypoxia-induced PC12 cells, and ß-Asarone addition led to a decline in RPPH1 expression. RPPH1 overexpression reversed the effect of ß-Asarone on hypoxia-induced injury in PC12 cells. Furthermore, we proved that RPPH1 could sponge miR-542-3p. Subsequently, death effector domain containing 2 (DEDD2) was proven as the downstream gene of RPPH1/miR-542-3p axis. Eventually, the whole regulation mechanism of RPPH1/miR-542-3p/DEDD2 axis was testified through rescue assays. The impacts of ß-Asarone on hypoxia-induced PC12 cells could be countervailed by RPPH1 augment, which was also discovered to be neutralized in response to miR-542-3p overexpression or DEDD2 depletion. These findings offered a novel perspective for understanding neuroprotection.

Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma.

Tumor heterogeneity has been associated with immunotherapy and targeted drug resistance in hepatocellular carcinoma (HCC). However, communications between tumor and cytotoxic cells are poorly understood to date. In the present study, thirty-one clusters of cells were discovered in the tumor tissues and adjacent tissues through single-cell sequencing. Moreover, the quantity and function exhaustion of cytotoxic cells was observed to be induced in tumors by the TCR and apoptosis signal pathways. Furthermore, granzyme failure of cytotoxic cells was observed in HCC patients. Importantly, the GZMA secreted by cytotoxic cells was demonstrated to interact with the F2R expressed by the tumor cells both in vivo and in vitro. This interaction induced tumor suppression and T cell-mediated killing of tumor cells via the activation of the JAK2/STAT1 signaling pathway. Mechanistically, the activation of JAK2/STAT1 signaling promoted apoptosis under the mediating effect of the LDPRSFLL motif at the N-terminus of F2R, which interacted with GZMA. In addition, GZMA and F2R were positively correlated with PD-1 and PD-L1 in tumor tissues, while the expressions of F2R and GZMA promoted PD-1 mAb-induced tumor suppression in both mouse model and HCC patients. Finally, in HCC patients, a low expression of GZMA and F2R in the tumor tissues was correlated with aggressive clinicopathological characteristics and poor prognosis. Collectively, GZMA-F2R communication inefficient induces deficient PD-1 mAb therapy and provide a completely novel immunotherapy strategy for tumor suppression in HCC patients.

Construction and Biocompatibility Evaluation of Fibroin/Sericin-Based Scaffolds.

Because tissue responses to implants determine the success or failure of tissue engineering products, fibroin/sericin-based scaffolds including bionic silk scaffolds, native silk fibers, fibroin fibers, and regenerated fibroin have been fabricated, and their biocompatibility was investigated. Fibroin/sericin-based scaffolds were characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD). Bionic silk scaffolds were beneficial to silk fiber formation through self-assembly. Histological and immunofluorescent staining analysis demonstrated that bionic silk scaffolds did not show significant inflammatory responses. Immunization analysis showed that soluble fibroin and sericin did not show obvious immunogenicity. This work supplied an effective approach to design fibroin/sericin-based scaffolds for tissue engineering and drug delivery.

Immune Cell-Derived Extracellular Vesicles - New Strategies in Cancer Immunotherapy.

Immune cell-derived extracellular vesicles (EVs) have increasingly become the focus of research due to their unique characteristics and bioinspired applications. They are lipid bilayer membrane nanosized vesicles harboring a range of immune cell-derived surface receptors and effector molecules from parental cells. Immune cell-derived EVs are important mediators of intercellular communication that regulate specific mechanisms of adaptive and innate immune responses. However, the mechanisms underlying the antitumor effects of EVs are still being explored. Importantly, immune cell-derived EVs have some unique features, including accessibility, storage, ability to pass through blood-brain and blood-tumor barriers, and loading of various effector molecules. Immune cell-derived EVs have been directly applied or engineered as potent antitumor vaccines or for the diagnosis of clinical diseases. More research applications involving genetic engineering, membrane engineering, and cargo delivery strategies have improved the treatment efficacy of EVs. Immune cell-derived EV-based therapies are expected to become a separate technique or to complement immunotherapy, radiotherapy, chemotherapy and other therapeutic modalities. This review aims to provide a comprehensive overview of the characteristics and functions of immune cell-derived EVs derived from adaptive (CD4+ T, CD8+ T and B cells) and innate immune cells (macrophages, NK cells, DCs, and neutrophils) and discuss emerging therapeutic opportunities and prospects in cancer treatment.

The Intracellular Mechanism of Berberine-Induced Inhibition of CYP3A4 Activity.

BACKGROUND: Berberine (BBR) is an isoquinoline alkaloid extracted from the Chinese medicine, exerting a variety of pharmacological effects. BBR is partially metabolized by cytochrome 3A4 (CYP3A4) in vivo. Some reports indicated that BBR could inhibit the activity of CYP3A4. However, the underlying mechanisms are not completely understood. CYP3A4 is reported to be transcriptionally regulated by two nuclear receptors, nuclear transcription X receptor (PXR) and constitutive androstane receptor (CAR), and degraded via the ubiquitin-proteasome system. Hence, we tried to explore the mechanisms of CYP3A4 inhibition on both transcriptive and protein levels. METHODS: Western Blot, RT-PCR and Co-immunoprecipitation were used to perform the experiments. RESULTS: Our results showed that BBR inhibited the transcription of CYP3A4 gene by downregulating PXR. In addition, BBR accelerated the degradation of CYP3A4 protein via polyubiquitination pathway. CONCLUSION: These findings may lead to the determination of novel drug-drug interactions with BBR, and contribute to future clinical application of BBR.

Systematic calibration method based on acceleration and angular rate measurements for fiber-optic gyro SINS.

A simple systematic calibration method based on acceleration and angular rate measurements is introduced for the fiber-optic gyro strapdown inertial navigation system in this paper. Meanwhile, a unified mathematical framework and an iterative calculation method are designed for the systematic calibration method. Using this method, one can estimate the fiber-optic gyro inertial measurement unit (FOG IMU) parameters both at a manufacturer's facility and in the field. In order to get all FOG IMU parameters, a procedure adopted based on this approach consists of two stages: First, FOG IMU raw data (accelerometer and gyro readouts) are accumulated in 19 specified FOG IMU positions. Second, the accumulated data are processed by special software to estimate all FOG IMU parameters. In addition, observability analysis of the method in 19 specified FOG IMU positions is done without the limitation of FOG IMU's initial orientation, and this analysis provides theoretical support for the application in a complex terrain. Moreover, the influence of gravity disturbance is analyzed for the first time. The analysis and experiment results show that the systematic calibration method provided by this work can meet the requirement of FOG IMU calibration.

Upregulation of microRNA-155 Enhanced Migration and Function of Dendritic Cells in Three-dimensional Breast Cancer Microenvironment.

Background: Dendritic cells (DCs) play an essential role in the induction and regulation of immune responses, including the activation of effector T lymphocytes for the eradication of cancers. However, the tumor microenvironment (TME) often leads to DCs dysfunction due to their immature state. MicroRNA-155 (miR-155) has emerged as a typical multifunctional gene regulator associated with immune system development and immune cell activation and differentiation.Methods: In this study, a three-dimensional TME model that closely mimics the microenvironment of breast cancer was prepared. MiR-155 overexpression and control vectors were constructed using lentivirus. The relative expression of miR-155 was determined by qRT-PCR. Cell viability, antigen uptake and cell surface marker expression were analyzed by live-dead staining and flow cytometry. The migration ability of bone marrow-derived DCs (BMDCs) was qualified by transwell assay. A mixed lymphocyte culture assay was used to assess T cell-specific proliferation. Cytokine levels were determined by ELISA.Results: We found that the expression of miR-155 in DCs was inhibited by the TME. Furthermore, upregulation of miR-155 enhanced the migration ability, uptake of antigen and elevated the expression of the mature DCs markers CD80 and MHCII. More importantly, overexpression of miR-155 in DCs significantly induced T cell proliferation and IFN-γ and IL-2 secretion.Conclusion: MiR-155 is a potential molecular regulator that may improve the efficacy of DCs-based tumor immunotherapy.

The exosomes derived from CAR-T cell efficiently target mesothelin and reduce triple-negative breast cancer growth.

Genetically engineered T cells expressing a chimeric antigen receptor (CAR) have rapidly developed into a powerful and innovative therapeutic modality for cancer patients. However, the problem of dose-dependent systemic toxicity cannot be ignored. In this study, exosomes derived from mesothelin (MSLN)-targeted CAR-T cells were isolated, and we found that they maintain most characteristics of the parental T cells, including surface expression of the CARs and CD3. Furthermore, CAR-carrying exosomes significantly inhibited the growth of both endogenous and exogenous MSLN-positive triple-negative breast cancer (TNBC) cells. The expression of the effector molecules perforin and granzyme B may be a mechanism of tumor killing. More importantly, a highly effective tumor inhibition rate without obvious side effects was observed with the administration of CAR-T cell exosomes in vivo. Thus, the use of CAR-T cell exosomes has great therapeutic potential against MSLN-expressing TNBC.

Progress and prospects of biomarkers in primary liver cancer (Review).

Tumor biomarkers are important in the early screening, diagnosis, therapeutic evaluation, recurrence and prognosis prediction of tumors. Primary liver cancer is one of the most common malignant tumors; it has high incidence and mortality rates and seriously endangers human health. The main pathological types of primary liver cancer include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined HCC­cholangiocarcinoma (cHCC­CC). In the present review, a systematic outline of the current biomarkers of primary liver cancer is presented, from conventional blood biomarkers, histochemical biomarkers and potential biomarkers to resistance­associated biomarkers. The important relationships are deeply elucidated between biomarkers and diagnosis, prognosis, clinicopathological features and resistance, as well as their clinical significance, in patients with the three main types of primary liver cancer. Moreover, a summary of several important biomarker signaling pathways is provided, which is helpful for studying the biological mechanism of liver cancer. The purpose of this review is to provide help for clinical or medical researchers in the early diagnosis, differential diagnosis, prognosis and treatment of HCC.