Hepatocellular carcinoma (HCC) most often develops in patients infected with hepatitis B or hepatitis C virus. Differential gene expression profiling is useful for investigating genes associated with ...lymph node metastasis (LNM). We screened genes to identify potential biomarkers for LNM in HCC.
RNA was extracted from formalin-fixed specimens of paired intratumoral and peritumoral tissues of patients with lymph node-positive (n = 36) or negative (n = 36) HCC. A cDNA-mediated annealing, selection, extension, and ligation assay was done with an array of 502 known cancer-related genes to identify differentially expressed genes in 20 pairs of patients with or without LNM. Candidate biomarkers were evaluated by using immunohistochemistry and tissue microarrays in an independent cohort of 309 HCC patients who had undergone hepatectomy. Of the 309 patients, 235 (76.1%) patients were infected with hepatitis B.
Compared with lymph node-negative patients, lymph node-positive patients had 17 overexpressed genes and 19 underexpressed genes in intratumoral tissues, and 25 overexpressed genes and 22 underexpressed genes in peritumoral tissues. Hypoxia-inducible factor (HIF)-1α, VEGF, and matrix metalloproteinase (MMP)-2 were selected for analysis in the cohort of 309 HCC patients. We found that intratumoral protein levels of HIF-1α, VEGF, and MMP-2 were independent risk factors for developing LNM.
We identified 83 cancer genes that were differentially expressed in lymph node-positive and lymph node-negative HCC. Our findings show that the combination of intratumoral HIF-1α, VEGF, and MMP-2 may be useful as a molecular prediction model for LNM.
Most hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage; however, the effect of systemic therapy on advanced HCC remains undetermined. Therefore, new treatment targets must be ...identified. We analyzed Gene Expression Omnibus datasets from two HCC patient cohorts and found that NT5DC2 was associated with vascular invasion and poor survival. In two hepatoma cell lines, NT5DC2 overexpression promoted HCC cell proliferation and clone formation in vitro and promoted tumor growth in vivo. Coimmunoprecipitation assays and liquid chromatography with tandem mass spectrometry analysis revealed that NT5DC2 bound directly to epidermal growth factor receptor (EGFR). NT5DC2 upregulated EGFR expression by downregulating EGFR ubiquitination and preventing its degradation via the ubiquitin-proteasome pathway but did not upregulate its transcription. EGFR upregulation activated downstream signal transduction, which played a critical role in the protumor effects of NT5DC2. Erlotinib, a small-molecule inhibitor of EGFR, blocked the effect of NT5DC2 in promoting HCC cell proliferation. In a cohort of 79 patients who underwent curative resection for HCC, NT5DC2 expression in the tumors was associated with larger tumors and microvascular invasion. NT5DC2 expression was also independently associated with recurrence-free survival. The present study demonstrated for the first time that NT5DC2 promotes tumor cell proliferation in HCC and may serve as a potential molecular target for treating HCC. EGFR blockage could be used to treat selected patients with NT5DC2 upregulation.
Numerous clinical models have been proposed to evaluate and predict recurrence and survival of hepatocellular carcinoma (HCC) patients in different stages after resection, but no model for very ...early-stage HCC.
The data of 661 very early-stage HCC patients after curative resection in our hospital were retrospectively reviewed. Kaplan-Meier curves and Cox proportional hazards regression models were used to analyze recurrence and survival. The risk classifications for recurrence and survival were established by using classification and regression tree analysis. The nomograms were constructed and validated using bootstrap resampling and an independent 186-patient validation cohort from the same institution.
According to the results of multivariate analysis for prognosis after resection, decision trees and 3-stratification classifications that satisfactorily determined the risk of recurrence and survival were established. Based on these two risk classifications, a six-factor nomogram for predicting recurrence and a six-factor nomogram for predicting survival were created. The concordance indexes were 0.64 for recurrence nomogram, with a 95% confidence interval of 0.60–0.67, and 0.76 for survival nomogram, with a 95% confidence interval of 0.70–0.82. The calibration curves showed good agreement between the predictions made by the nomograms and the actual survival outcomes. These predicting results for recurrence and survival were better than three common classical HCC stages and were confirmed in the independent validation cohort.
The 3-stratification classifications enabled satisfactory risk evaluations of recurrence and survival, and the nomograms showed considerably accurate predictions of the risk of recurrence and survival in very early-stage HCC patients after curative resection.
The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Recently, we have identified that a ...hepatic stem cell marker, epithelial cell adhesion molecule (EpCAM), may serve as an early biomarker of HCC because its expression is highly elevated in premalignant hepatic tissues and in a subset of HCC. In this study, we aimed to identify novel HCC subtypes that resemble certain stages of liver lineages by searching for EpCAM-coexpressed genes. A unique signature of EpCAM-positive HCCs was identified by cDNA microarray analysis of 40 HCC cases and validated by oligonucleotide microarray analysis of 238 independent HCC cases, which was further confirmed by immunohistochemical analysis of an additional 101 HCC cases. EpCAM-positive HCC displayed a distinct molecular signature with features of hepatic progenitor cells including the presence of known stem/progenitor markers such as cytokeratin 19, c-Kit, EpCAM, and activated Wnt-beta-catenin signaling, whereas EpCAM-negative HCC displayed genes with features of mature hepatocytes. Moreover, EpCAM-positive and EpCAM-negative HCC could be further subclassified into four groups with prognostic implication by determining the level of alpha-fetoprotein (AFP). These four subtypes displayed distinct gene expression patterns with features resembling certain stages of hepatic lineages. Taken together, we proposed an easy classification system defined by EpCAM and AFP to reveal HCC subtypes similar to hepatic cell maturation lineages, which may enable prognostic stratification and assessment of HCC patients with adjuvant therapy and provide new insights into the potential cellular origin of HCC and its activated molecular pathways.
Endothelial cells (ECs) are critical for angiogenesis, and microRNA plays important roles in this process. In this study, we investigated the function and mechanism of miR-302c in the process of ...endothelial-mesenchymal transition (EndMT) in ECs. When miR-302c was overexpressed in HUVECs, the motility of the HUVECs was weakened; the expression levels of EndMT markers were also changed: vascular endothelial (VE)-cadherin was up-regulated, whereas β-catenin, FSP1, and α-SMA were down-regulated. Further in vivo and in vitro experiments showed that the growth of HCC was inhibited when co-cultured or co-injected with HUVECs overexpressing miR-302c. On the contrary, when miR-302c was suppressed in HUVECs, the opposite results were observed. Reporter assays showed that miR-302c inhibited metadherin (MTDH) expression through directly binding to its 3'UTR. In addition, compared to ECs isolated from normal liver tissues of HCC patients, ECs isolated from tumor tissues expressed markedly low levels of miR-302c but high levels of MTDH. These results suggest that EC-specific miR-302c suppresses tumor growth in HCC through MTDH-mediated inhibition of EndMT. MTDH and miR-302c might provide a new strategy for anti-angiogenic therapy in HCC.
Abundant evidence points to the Cretaceous crust-mantle interaction and plate subduction in the Gan-Hang Tectonic Belt (GHTB), southeastern China, but the evolutionary process remains poorly ...constrained. Here we conduct a comprehensive study on Daqiaowu granitic porphyry and diabase dikes in the eastern GHTB, in conjunction with previous studies on simultaneous felsic and mafic rocks along the GHTB, to demonstrate their petrogenesis and geodynamic evolutionary process. The Daqiaowu granitic porphyry (125 Ma), as well as the coeval granitic rocks, exhibits high zircon saturation temperatures, alkalis, 10
4
*Ga/Al ratios, and Zr + Nb + Ce + Y contents, concluding a distinctive belt of the Early Cretaceous (~137-125 Ma) A-type volcanic-intrusive rocks in the GHTB. Their ε
Nd
(t) and zircon ε
Hf
(t) values gradually increased through time from approximately −9.0 to −1.0 and −10.0 to +4.0, respectively, implying increasing contribution of mantle-derived components to their formation, and hence progressively intensified crust-mantle interaction in an intra-arc rift environment (a geodynamic transition stage from continental arc to back-arc) during the Early Cretaceous. This plausibility is further supported by the Early Cretaceous Daqiaowu diabase dikes and coeval mafic rocks which exhibit arc-like magmatic signatures and were derived from mantle wedge. In contrast, the Late Cretaceous mafic rocks show ocean island basalt-like geochemical characteristics, reflecting a depleted asthenosphere mantle source. This discrepancy of mantle sources concludes that the geodynamic setting in the GHTB may have basically transferred to back-arc regime in the Late Cretaceous. Thus, the Cretaceous geodynamic evolutionary process in the GHTB can be defined as the Early Cretaceous gradually intensified crust-mantle interaction in a geodynamic transition stage (from continental arc to back-arc extension) and the Late Cretaceous back-arc extensional setting.
In the recent decades, the incidence of hepatocellular carcinoma (HCC) has been found to be increasing in males in some countries. In China, HCC ranked second of cancer mortality since 1990s. ...Hepatitis B and C viruses (HBV and HCV) and dietary aflatoxin intake remain the major causative factors of HCC. Surgery plays a major role in the treatment of HCC, particularly for small HCC. Down-staging unresectable huge HCC to smaller HCC and followed by resection will probably be a new approach for further study. Liver transplantation is indicated for small HCC, however, some issues remain to be solved. Different modes of regional cancer therapy for HCC have been tried. Systemic chemotherapy has been disappointing in the past but the future can be promising. Biotherapy, such as cytokines, differentiation inducers, anti-angiogenic agents, gene therapy and tumor vaccine will probably play a role, particularly in the prevention of tumor recurrence. HCC invasiveness is currently the major target of study. Tremendous works have been done at the molecular level, which will provide clues for biomarker of HCC progression as well as targets for intervention.
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