Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma

Abstract

Although HCC is the third-leading cause of cancer-related deaths worldwide, there is only an elemental understanding of its molecular pathogenesis. In western countries, HCV infection is the main etiology underlying this cancer's accelerating incidence. To characterize the molecular events of the hepatocarcinogenic process, and to identify new biomarkers for early HCC, the gene expression profiles of 75 tissue samples were analyzed representing the stepwise carcinogenic process from preneoplastic lesions (cirrhosis and dysplasia) to HCC, including 4 neoplastic stages (very early HCC to metastatic tumors) from patients with HCV infection. We identified gene signatures that accurately reflect the pathological progression of disease at each stage. Eight genes distinguish between control and cirrhosis, 24 between cirrhosis and dysplasia, 93 between dysplasia and early HCC, and 9 between early and advanced HCC. Using quantitative real-time reverse-transcription PCR, we validated several novel molecular tissue markers for early HCC diagnosis, specifically induction of abnormal spindle-like, microcephaly-associated protein, hyaluronan-mediated motility receptor, primase 1, erythropoietin, and neuregulin 1. In addition, pathway analysis revealed dysregulation of the Notch and Toll-like receptor pathways in cirrhosis, followed by deregulation of several components of the Jak/STAT pathway in early carcinogenesis, then upregulation of genes involved in DNA replication and repair and cell cycle in late cancerous stages. Conclusion: These findings provide a comprehensive molecular portrait of genomic changes in progressive HCV-related HCC. (HEPATOLOGY 2007;45:938-947.)

MMSET is overexpressed in cancers: Link with tumor aggressiveness

“…Thus, we looked for whether MMSET expression could be associated with tumor progression and prognosis. MMSET was significantly overexpressed in oligodendroglioma grade III compared to grade II (P = .009) [11] ( Figure 1) in agreement with previous data [9]; in patients presenting advanced bladder carcinoma (grade II and III) compared to grade I in four independent studies (P = 4E-6, P = .0001, P = .004, P = .008) [19; 43; 44; 45]; in breast carcinoma grades II and III compared to grade I in four independent studies (P = 2.2E-6, P = 9.1E-4, P = .014, P = .017) [46; 47; 48; 49]; in advanced prostate carcinoma grades VII, VIII and IX compared to grade VI (P = 1.4E-4 [50]; in no differentiated hepatocellular carcinoma compared to differentiated hepatocellular carcinoma (P = 7.2E-5) [15]; in undifferentiated compared to differentiated head and neck cancer (P = .002) [17]; in undifferentiated compared to differentiated cervical carcinoma [51]; in advanced papillary renal cell carcinoma stages III and IV compared to stages I and II (P = .0039) [52] (Figure 1). Furthermore, as it has been demonstrated in MM, MMSET expression is associated with bad prognostic in others cancers (Figure 2).…”

“…The identification of the targets of MMSET and their role in cell growth and survival will be key to understanding how MMSET is associated with tumor development. MMSET gene expression in oligodendroglioma [9], bladder [19; 43; 44; 45], breast carcinoma [46; 47; 48; 49], prostate carcinoma [50], in hepatocellular carcinoma [15], head and neck cancer [17], cervical carcinoma [51], papillary renal cell carcinoma [52]. MMSET expression in alive patients with head and neck carcinoma, in dead patients with head and neck carcinoma [53], in MM patients with no relapse, in MM patients with relapse [54], in alive and dead patients with MM [54], in prostate carcinoma patients with no recurrence, prostate carcinoma patients with recurrence [50], in alive and dead patients with glioma [55].…”

The involvement of the transcription factor Yin Yang 1 in cancer development and progression

“…Fifteen publicly available gene expression datasets were analyzed. 28,[35][36][37][38][39][40][41][42][43][44][45][46][47][48] Gene expression patterns of YY1 in nine different types of tumor and the relative normal counterpart were extracted from the normalized datasets (Table 2). This analysis reveals that YY1 transcript levels are significantly higher in cancer tissues than in the relative normal counterparts for each cancer type analyzed.…”

Ras Promotes Growth by Alternative Splicing-Mediated Inactivation of the KLF6 Tumor Suppressor in Hepatocellular Carcinoma

“…Human HCCs were obtained as described recently 30,31 . A total of 67 fresh-frozen HCC samples from HCV-positive patients were analyzed in the study.…”