Showing papers by "Feng Shen published in 2011"

RNA-Seq Analyses Generate Comprehensive Transcriptomic Landscape and Reveal Complex Transcript Patterns in Hepatocellular Carcinoma

Abstract: RNA-seq is a powerful tool for comprehensive characterization of whole transcriptome at both gene and exon levels and with a unique ability of identifying novel splicing variants. To date, RNA-seq analysis of HBV-related hepatocellular carcinoma (HCC) has not been reported. In this study, we performed transcriptome analyses for 10 matched pairs of cancer and non-cancerous tissues from HCC patients on Solexa/Illumina GAII platform. On average, about 21.6 million sequencing reads and 10.6 million aligned reads were obtained for samples sequenced on each lane, which was able to identify >50% of all the annotated genes for each sample. Furthermore, we identified 1,378 significantly differently expressed genes (DEGs) and 24, 338 differentially expressed exons (DEEs). Comprehensive function analyses indicated that cell growth-related, metabolism-related and immune-related pathways were most significantly enriched by DEGs, pointing to a complex mechanism for HCC carcinogenesis. Positional gene enrichment analysis showed that DEGs were most significantly enriched at chromosome 8q21.3–24.3. The most interesting findings were from the analysis at exon levels where we characterized three major patterns of expression changes between gene and exon levels, implying a much complex landscape of transcript-specific differential expressions in HCC. Finally, we identified a novel highly up-regulated exon-exon junction in ATAD2 gene in HCC tissues. Overall, to our best knowledge, our study represents the most comprehensive characterization of HBV-related HCC transcriptome including exon level expression changes and novel splicing variants, which illustrated the power of RNA-seq and provided important clues for understanding the molecular mechanisms of HCC pathogenesis at system-wide levels.

Pathobiological features of small hepatocellular carcinoma: correlation between tumor size and biological behavior.

Abstract: Increasing evidence has suggested that tumor size is one of the independent prognostic factors of patients with hepatocellular carcinoma (HCC). However, the criteria used to determine when HCC should be classified as small remain controversial. Our objective was to evaluate the relationship between the size of HCC and its clinicopathological features. A retrospective study on 618 patients who underwent partial hepatectomy for solitary HCC was performed. These patients were divided into Groups 1–5 according to the tumor diameter: ≤1, 1.1–2, 2.1–3, 3.1–5 and >5 cm, respectively. The clinicopathological variables of the patients in each group were compared statistically. Except for the microHCC (≤1 cm) which differed significantly from the other four groups in the clinicopathological variables, almost no differences existed among HCC ranging from 1 to 3 cm, or HCCs > 3 cm. If ≤3 cm was used as the cut-off point for small HCC (SHCC), and >3 cm for large HCC (LHCC), significant differences (P 3 cm was one of the independent prognostic factors for both OS and RFS. The 3 cm cutoff seems to best determine the biological behavior and clinical prognosis of patients undergoing partial hepatectomy for early stage HCC. Overall, HCC smaller than 3 cm in diameter was closely related with a better prognosis which reflected the relatively benign pathobiological features at an early developmental stage. As HCC > 3 cm exhibited a tendency towards more aggressive behavior, we suggest that HCC ≤ 3 cm in diameter should be used as a critical size of SHCC at which curative treatment achieves better long-term survivals.

Autophagy in hypoxia protects cancer cells against apoptosis induced by nutrient deprivation through a beclin1‐dependent way in hepatocellular carcinoma

Abstract: Oxygen deficiency and nutrient deprivation widely exists in solid tumors because of the poor blood supply. However, cancer cells can survive this adverse condition and proliferate continuously to develop. To figure out the way to survive, we investigated the role of autophagy in the microenvironment in hepatocellular carcinoma. In order to simulate the tumor microenvironment more veritably, cells were cultured in oxygen-nutrient-deprived condition following a hypoxia preconditioning. As a result, cell death under hypoxia plus nutrient deprivation was much less than that under nutrient deprivation only. And the decreased cell death mainly attributed to the decreased apoptosis. GFP-LC3 and electron microscopy analysis showed that autophagy was significantly activated in the period of hypoxia preconditioning. However, autophagic inhibitor-3-MA significantly abrogated the apoptosis reduction in hypoxia, which implied the involvement of autophagy in protection of hepatocellular carcinoma cells against apoptosis induced by starvation. Furthermore, Beclin 1 was proved to play an important role in this process. siRNA targeting Beclin 1 was transfected into hepatocellular carcinoma cells. And both data from western blot detecting the expression of LC3-II and transmission microscopy observing the accumulation of autophagosomes showed that autophagy was inhibited obviously as a result of Beclin 1 knockdown. Besides, the decreased apoptosis of starved cells under hypoxia was reversed. Taken together, these results suggest that autophagy activated by hypoxia mediates the tolerance of hepatocellular carcinoma cells to nutrient deprivation, and this tolerance is dependent on the activity of Beclin 1.

Hepatocellular carcinoma expressing cholangiocyte phenotype is a novel subtype with highly aggressive behavior.

Abstract: Background The pathobiological features and surgical outcomes of patients with classical hepatocellular carcinoma (HCC)-expressing cholangiocyte markers that we named dual-phenotype HCC (DPHCC) remain unclear. The purpose of this study was to assess the association between the phenotype and surgicopathologic features of DPHCC.

Lens Culinaris Agglutinin-Reactive Fraction of Alpha-Fetoprotein as a Marker of Prognosis and a Monitor of Recurrence of Hepatocellular Carcinoma After Curative Liver Resection

Abstract: The aim of this study was to determine the role of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) as a prognostic marker and a monitor marker of recurrence after curative resection of hepatocellular carcinoma (HCC). From December 2002 to May 2004, 395 consecutive patients with HCC who underwent curative partial hepatectomy were included in the study. The tumor characteristics and clinical outcomes of patients with positive preoperative and postoperative AFP-L3 were compared with those with negative results. A high ratio of AFP-L3 to total AFP was an indicator of pathologic aggressiveness. Patients with positive preoperative AFP-L3 had significantly earlier recurrence (median time to recurrence 22.0 ± 2.4 months vs 45.0 ± 6.9 months, P < .001) when compared with those with negative preoperative results. Significantly more patients with continuously positive or negative-turn-positive AFP-L3 results after surgery developed recurrence, particularly distant metastases, when compared with patients with continuously negative AFP-L3 results. The overall and disease-free survivals were significantly shorter in the positive than the negative preoperative AFP-L3 group. The overall and disease-free survivals were significantly shorter in the continuously positive and the negative-turn-positive than the continuously negative postoperative AFP-L3 group. Positive preoperative AFP-L3 and continuously positive or negative-turn-positive AFP-L3 results after surgery predicted a more aggressive tumor behavior, higher tumor recurrence, and poorer clinical outcomes. HCC patients with an increased proportion of AFP-L3 to total AFP should be more aggressively treated and closely followed-up.