Identification of MACC1 as a novel prognostic marker in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Metastasis-associated in colon cancer-1 (<it>MACC1</it>) is a newly identified gene that plays a role in colon cancer metastasis through upregulation of c-MET proto-oncogene (c-MET). However, the value of <it>MACC1 </it>as a potential biomarker for hepatocellular carcinoma (HCC) remains unknown.</p> <p>Methods</p> <p><it>MACC1 </it>mRNA expression in 128 HCC tissues was examined by quantitative polymerase chain reaction. To show the potential correlation of <it>MACC1 </it>and c-MET, c-MET was also analysed.</p> <p>Results</p> <p><it>MACC1 </it>was more highly expressed in HCC than in non-HCC tissues (<it>P </it>= 0.009). High <it>MACC1 </it>expression was significantly increased in cases with high alpha fetoprotein (AFP) (<it>P </it>= 0.025). A positive correlation was found between <it>MACC1 </it>and c-MET mRNAs (r = 0.235, <it>P </it>= 0.009). Both univariate and multivariate analyses revealed that <it>MACC1 </it>expression was associated with overall survival (OS) and disease-free survival (DFS). Moreover, stratified analysis showed that tumour-node-metastasis (TNM) stage I patients with high <it>MACC1 </it>levels had shorter OS and DFS than those with low <it>MACC1</it>.</p> <p>Conclusions</p> <p><it>MACC1 </it>may identify low- and high-risk individuals with HCC and be a valuable indicator for stratifying the prognosis of TNM stage I patients. <it>MACC1 </it>may serve as a novel biomarker for HCC.</p

Delineating the molecular landscape of different histopathological growth patterns in colorectal cancer liver metastases

BackgroundHistopathological growth patterns (HGPs) have shown important prognostic values for patients with colorectal cancer liver metastases, but the potential molecular mechanisms remain largely unknown.MethodsWe performed an exploratory analysis by conducting the RNA sequencing of primary colorectal lesions, colorectal liver metastatic lesions and normal liver tissues.FindingsWe found that desmoplastic HGPs of the metastatic lesions were significantly enriched in EMT, angiogenesis, stroma, and immune signaling pathways, while replacement HGPs were enriched in metabolism, cell cycle, and DNA damage repair pathways. With the exception of immune-related genes, the differentially expressed genes of the two HGPs from colorectal liver metastases were mostly inherited from the primary tumor. Moreover, normal liver tissue in the desmoplastic HGP subgroup was markedly enriched in the fibrinous inflammation pathway.ConclusionsWe surmised that HGPs are observable morphological changes resulting from the regulation of molecular expressions, which is the combined effect of the heterogeneity and remodeling of primary tumors seeds and liver soils

A novel NHEJ gene signature based model for risk stratification and prognosis prediction in hepatocellular carcinoma

Abstract Background Non-homologous DNA end joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in human. However, the relationship between NHEJ pathway and hepatocellular carcinoma (HCC) is unclear. We aimed to explore the potential prognostic role of NHEJ genes and to develop an NHEJ-based prognosis signature for HCC. Methods Two cohorts from public database were incorporated into this study. The Kaplan–Meier curve, the Least absolute shrinkage and selection operator (LASSO) regression analysis, and Cox analyses were implemented to determine the prognostic genes. A NHEJ-related risk model was created and verified by independent cohorts. We derived enriched pathways between the high- and low-risk groups using Gene Set Enrichment Analysis (GSEA). CIBERSORT and microenvironment cell populations-counter algorithm were used to perform immune infiltration analysis. XRCC6 is a core NHEJ gene and immunohistochemistry (IHC) was further performed to elucidate the prognostic impact. In vitro proliferation assays were conducted to investigate the specific effect of XRCC6. Results A novel NHEJ-related risk model was developed based on 6 NHEJ genes and patients were divided into distinct risk groups according to the risk score. The high-risk group had a poorer survival than those in the low-risk group (P < 0.001). Meanwhile, an obvious discrepancy in the landscape of the immune microenvironment also indicated that distinct immune status might be a potential determinant affecting prognosis as well as immunotherapy reactiveness. High XRCC6 expression level associates with poor outcome in HCC. Moreover, XRCC6 could promote HCC cell proliferation in vitro. Conclusions In brief, this work reveals a novel NHEJ-related risk signature for prognostic evaluation of HCC patients, which may be a potential biomarker of HCC immunotherapy

Clinical features and outcome of multiple primary malignancies involving hepatocellular carcinoma: A long-term follow-up study

Abstract Background The prolonged survival of individuals diagnosed with cancer has led to an increase in the number of secondary primary malignancies. We undertook to perform a definitive study to characterize and predict prognosis of multiple primary malignancies (MPM) involving hepatocellular carcinoma (HCC), due to the scarcity of such reports. Methods Clinicopathological data were analyzed for 68 MPM patients involving HCC, with 35 (target group) underwent curative liver resection. Additional 140 HCC-alone patients with hepatectomy were selected randomly during the same period as the control group. Results Of the 68 patients with extrahepatic primary malignancies (EHPM), 22 were diagnosed synchronously with HCC, and 46 metachronously. The most frequent EHPM was nasophargeal carcinoma, followed by colorectal and lung cancer. Univariate analysis demonstrated that synchronous (P = 0.008) and non-radical treatment for EHPM (P P = 0.607, P = 0.131, respectively). Conclusions Curative treatment is an independent predictive factor for OS and HCC-specific OS, and should been taken into account both for synchronous and metachronous patients. MPM patients involving HCC should not be excluded from radical resection for HCC.</p

Impact of follow-up interval on patients with hepatocellular carcinoma after curative ablation

Abstract Background The optimal follow-up strategy after curative thermal ablation of hepatocellular carcinoma (HCC) remains unclear. Methods We retrospectively analyzed a prospective series of 616 patients who underwent curative thermal ablation for HCC within the Milan criteria. Multivariate Cox model was used to identify independent predictive factors for recurrence; accordingly, patients were stratified into 2 groups with different relapse risks: a low-risk group (solitary tumor ≤3 cm) and a high-risk group (multiple tumors ≤3 cm or solitary tumor between 3 and 5 cm). Then, patients were classified into short- (< 4 months) or long-interval (4–6 months) surveillance groups according to follow-up intensity within the first 2 years after ablation. The overall survival (OS) of patients were compared between short- and long-interval groups in low- or high-risk groups, as well as the stage of recurrent tumors and the proportion of patients who received curative-intent retreatments. Results In the low-risk group, 54 (83.0%) and 18 (72.0%) of patients exhibited early relapse at the Barcelona Clinic Liver Cancer (BCLC) 0/A stage in the short- and long-interval groups, respectively (P = 0.172); accordingly, 44 (77.2%) and 18 (81.8%) of patients received curative-intent retreatment (P = 0.086) after recurrence. Hence, 5-year OS was similar between short- and long-interval groups (80.4% vs. 77.5%, P = 0.400) in low-risk patients. However, in the high-risk group, patients with a short interval exhibited early relapse more frequently at the BCLC 0/A stage (83% vs. 72%, P = 0.028), with a trend showing that the corresponding proportion of patients who received curative-intent retreatment greater than that in the long-interval group (64.2% vs. 37.5%, P = 0.087). Moreover, the short-interval group showed better 5-year OS than the long-interval group in high-risk patients (69.9% vs. 42.7%, P = 0.020). Conclusions Compared to a short surveillance interval, a long surveillance interval does not reduce OS in low-risk patients; however, a long surveillance interval compromises OS in high-risk patients

Overexpression of amplified in breast cancer 1 (AIB1) gene promotes lung adenocarcinoma aggressiveness in vitro and in vivo by upregulating C-X-C motif chemokine receptor 4

Abstract Background We previously found that overexpression of the gene known as amplified in breast cancer 1 (AIB1) was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma. However, the role of AIB1 in that malignancy remains unknown. The present study aimed to investigate the function of AIB1 in the process of lung adenocarcinoma cell metastasis. Methods A series of in vivo and in vitro assays were performed to elucidate the function of AIB1, while real-time PCR and Western blotting were utilized to identify the potential downstream targets of AIB1 in the process of lung adenocarcinoma metastasis. Rescue experiments and in vitro assays were performed to investigate whether the invasiveness of AIB1-induced lung adenocarcinoma was mediated by C-X-C motif chemokine receptor 4 (CXCR4). Results The ectopic overexpression of AIB1 in lung adenocarcinoma cells substantially enhanced cell migration and invasive abilities in vitro and tumor metastasis in vivo, whereas the depletion of AIB1 expression substantially inhibited lung adenocarcinoma cell migration and invasion. CXCR4 was identified as a potential downstream target of AIB1 in lung adenocarcinoma. The knockdown of AIB1 greatly reduced CXCR4 gene expression at both the transcription and protein levels, whereas the knockdown of CXCR4 in cells with AIB1 ectopic overexpression diminished AIB1-induced migration and invasion in vitro and tumor metastasis in vivo. Furthermore, we found a significant positive association between the expression of AIB1 and CXCR4 in lung adenocarcinoma patients (183 cases), and the co-overexpression of AIB1 and CXCR4 predicted the poorest prognosis. Conclusions These findings suggest that AIB1 promotes the aggressiveness of lung adenocarcinoma in vitro and in vivo by upregulating CXCR4 and that it might be usable as a novel prognostic marker and/or therapeutic target for this disease