Pinzhu Huang

Identification of MACC1 as a novel prognostic marker in hepatocellular carcinoma

BackgroundMetastasis-associated in colon cancer-1 (MACC1) 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 MACC1 as a potential biomarker for hepatocellular carcinoma (HCC) remains unknown.MethodsMACC1 mRNA expression in 128 HCC tissues was examined by quantitative polymerase chain reaction. To show the potential correlation of MACC1 and c-MET, c-MET was also analysed.ResultsMACC1 was more highly expressed in HCC than in non-HCC tissues (P = 0.009). High MACC1 expression was significantly increased in cases with high alpha fetoprotein (AFP) (P = 0.025). A positive correlation was found between MACC1 and c-MET mRNAs (r = 0.235, P = 0.009). Both univariate and multivariate analyses revealed that MACC1 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 MACC1 levels had shorter OS and DFS than those with low MACC1.ConclusionsMACC1 may identify low- and high-risk individuals with HCC and be a valuable indicator for stratifying the prognosis of TNM stage I patients. MACC1 may serve as a novel biomarker for HCC.

CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies resistant to current chemotherapies or radiotherapies, which makes it urgent to identify new therapeutic targets for HCC. In this study, we found that checkpoint kinase 1 (CHK1) was frequently overexpressed and correlated with poor clinical outcome in patients with HCC. We further showed that the CHK1 inhibitor GÖ6976 was capable of sensitizing HCC cells to cisplatin, indicating that CHK1 may have oncogenic function in HCC. We found that CHK1 phosphorylated the tumor suppressor spleen tyrosine kinase (L) (SYK[L]) and identified the phosphorylation site at Ser295. Furthermore, CHK1 phosphorylation of SYK(L) promoted its subsequent proteasomal degradation. Expression of a nonphosphorylated mutant of SYK(L) was more efficient at suppressing proliferation, colony formation, mobility, and tumor growth in HCC lines. Importantly, a strong inverse correlation between the expression levels of CHK1 and SYK(L) was observed in patients with HCC. Collectively, our data demonstrate that SYK(L) is a substrate of CHK1 in tumor cells and suggest that targeting the CHK1/SYK(L) pathway may be a promising strategy for treating HCC.

Role of Sox2 and Oct4 in predicting survival of hepatocellular carcinoma patients after hepatectomy

OBJECTIVES The present study was aimed to explore the prognostic strength of Sox2 and Oct4A in hepatocellular carcinoma (HCC). DESIGN AND METHODS We investigated the expression of Sox2 and Oct4A in five hepatoma cell lines, one immortalized normal liver cell line, HCC tissues with matched nontumorous liver tissues and normal liver tissues by reverse transcription-polymerase chain reaction. RESULTS Sox2 and Oct4A mRNA were overexpressed in hepatoma cell lines and tumor tissues. Sox2 or Oct4A positive expression was significantly associated with an aggressive phenotype. Both univariate and multivariate analyses revealed that Sox2 or Oct4A was an independent prognostic factor for HCC. When using subgroup analysis, the patients with a co-expression of Sox2/Oct4A had the poorest prognosis. Further analysis demonstrated that Sox2 alone or Sox2/Oct4A could stratify outcome in HCC patients with early stage. CONCLUSIONS Sox2 and Oct4A can be novel predictors of poor prognosis for patients undergoing resection of HCC.

Expression of variant isoforms of the tyrosine kinase syk determines the prognosis of hepatocellular carcinoma

The spleen tyrosine kinase (SYK) has been reported as a novel biomarker for human hepatocellular carcinoma, but the functional contributions of its two isoforms SYK(L) and SYK(S) are undefined. In this study, we investigated their biologic functions and possible prognostic values in hepatocellular carcinoma. SYK(L) was downregulated in 38% of human specimens of hepatocellular carcinoma examined, whereas SYK(S) was detectable in 40% of these specimens but not in normal liver tissue samples without cirrhosis. SYK(S) expression correlated with pathologic parameters characteristic of tumor metastasis, including multiple tumors (P = 0.003) and vascular invasion (P = 0.001). Further, SYK(S) was specifically associated with epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma specimens. Functional studies showed that SYK(S) promoted tumor growth, suppressed apoptosis, and induced EMT through the extracellular signal-regulated kinase pathway, countering the opposite effects of SYK(L). Patients with SYK(L(+)/S(-)) tumors exhibited longer overall survival and time to recurrence than those with SYK(L(-)/S(-)) or SYK(L(+)/S(+)) tumors (P < 0.001). Taken together, our findings showed that SYK(S) enhances invasion, whereas SYK(L) inhibits metastasis in hepatocellular carcinoma. We suggest that SYK(L) downregulation or SYK(S) elevation are strong predictors of poor survival in patients with hepatocellular carcinoma, indicative of a need for aggressive therapeutic intervention.

Expression and prognostic significance of CIP2A mRNA in hepatocellular carcinoma and nontumoral liver tissues

Objective: This study was undertaken to determine the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in predicting prognosis of hepatocellular carcinoma (HCC). Methods: CIP2A mRNA level of 136 pairs of tumor and nontumoral liver tissues of HCC patients after hepatectomy were investigated by quantitative real-time reverse transcription polymerase chain reaction. Results: Intratumoral CIP2A mRNA was not associated with patients’ prognosis. However, nontumoral CIP2A mRNA, which was correlated with lack of tumor encapsulation, poor tumor differentiation, intrahepatic metastasis, and high tumor-node-metastasis stage was an independent risk factor for overall survival and recurrence-free survival. Conclusions: Nontumoral CIP2A mRNA expression might serve as a novel biomarker for HCC patients undergoing resection.

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

BackgroundThe 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.MethodsClinicopathological 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.ResultsOf 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 < 0.001) were significant risk factors associated with poorer overall survival (OS). While, Cox modeling revealed that the treatment modality for EHPM, but not the synchronous/metachronous determinant, was an independent factor for OS, and that therapeutic option for HCC was an independent factor for HCC-specific OS. Moreover, no HCC-specific overall and recurrence-free survival benefit were observed in the control group when compared with that of the target group (P = 0.607, P = 0.131, respectively).ConclusionsCurative 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.

Hepatectomy for hepatocellular carcinoma patients with macronodular cirrhosis

Objective Patients with hepatocellular carcinoma (HCC) presenting with nonmicronodular or micronodular cirrhosis are usually treated by hepatectomy. The value of resection for patients with hepatitis B virus-related macronodular cirrhosis, however, remains unknown because of potentially fatal complications of this procedure. Methods Clinicopathological data were analyzed for 85 resected HCC patients with hepatitis B virus-related macronodular cirrhosis. An additional 255 patients with nonmicronodular and micronodular cirrhosis were randomly selected during the same period as the control group. Results Compared with nonmicronodular and micronodular cirrhosis patients, macronodular cirrhotic patients exhibited elevated alanine aminotransferase, aspartate aminotransferase, and &ggr;-glutamyltransferase levels, higher Child–Pugh classification, higher indocyanine green retention rate at 15 min (ICG R15), and more number of total complications. No significant differences were observed between the two groups with regard to major complications, mortality, overall survival, and recurrence-free survival. The morbidity rate was relatively low in patients exhibiting low ICG R15 (<10%). Cox analysis identified small tumors (⩽5 cm) and radical resection as independent prognostic factors that could predict long-term overall survival. Radical resection can result in high recurrence-free survival in macronodular cirrhotic patients. Conclusion Resection is safe for macronodular cirrhotic HCC patients, and radical resection provides a positive outcome. Small-sized patients are good candidates for hepatectomy. Macronodular cirrhosis should not rule out hepatectomy in patients with low ICG R15.

Aberrant expression of long noncoding RNA SNHG15 correlates with liver metastasis and poor survival in colorectal cancer: HUANG et al.

Long noncoding RNAs (lncRNAs) play a critical role in the initiation and progression of colorectal cancer (CRC), but little is known about the function of lncRNAs in the colorectal liver metastasis (CLM). This study was designed to identify specific lncRNAs correlating to liver metastasis of CRC, and to further assess their clinical value. Seventeen patients with primary CRC lesions, adjacent normal mucosa, and synchronous liver metastases lesions were divided into discovery set (six patients) and test set (11 patients). Transcriptome sequencing (RNAseq) was used to screen differential expression of lncRNAs in the discovery set. Based on bioinformatics data, quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR) was used to verify the target lncRNA in test set. The relationships between target lncRNA and clinical values were analysed in an expanded validation set of additional 91 patients. 23 upregulated and 14 downregulated lncRNAs were detected for distinguishing synchronous liver metastases, primary CRC lesions from adjacent normal mucosa in the RNAseq set. The expression levels of four lncRNAs in the 37 lncRNA signature were verified by qRT‐PCR in the test set. Compared with the paired normal mucosa, high expression levels of lnc‐small‐nucleolar RNA host gene 15 (SNHG15) were detected not only in primary CRC lesions but also in liver metastases lesions in the test set. Furthermore, in the expanded validation set, high expression of lnc‐SNHG15 was significantly associated with lymph‐node metastasis and liver metastasis (p < 0.05), and patients displaying high lncRNA‐SNHG15 expression exhibited a shorter median overall survival duration than those displaying low expression (30.7 vs. 35.2 months; p = 0.003). Multivariate analyses demonstrated that lncRNA‐SNHG15 overexpression may serve as a poor prognostic biomarker for CRC patients (p = 0.049; Coxs regression: 2.731). Lnc‐SNHG15 overexpression was significantly associated with CLM and high‐expression of lnc‐SNHG15 in CRC was an independent predictor of poor survival.

Associations between the cyclooxygenase-2 expression in circulating tumor cells and the clinicopathological features of patients with colorectal cancer: CAI et al.

While previous studies have shown that the number of circulating tumor cells (CTCs) alone is not sufficient to reflect tumor progression and that cyclooxygenase‐2 (COX‐2) expression is correlated with colorectal cancer (CRC) metastasis, COX‐2 expression status and its potential functions in CTCs of CRC patients are unknown. Here, epithelial‐mesenchymal transition (EMT) phenotype‐based subsets of CTCs and the COX‐2 expression status in CTCs were identified and their potential clinical values were assessed in 91 CRC patients. CTCs were enumerated in peripheral blood and subsets of CTCs (epithelial [eCTCs], mesenchymal [mCTCs], and biophenotypic [bCTCs]) and the COX‐2 expression status were determined using the RNA in situ hybridization method. CTCs were detected in 80.2% (73 of 91) patients. Neither the total CTC nor eCTC numbers were found to significantly associate with any of the clinicopathological features. However, the number of mCTCs was significantly associated with distance metastasis (P = 0.035) and had a trend of being associated with lymph node metastasis ( P = 0.055). Among the 73 patients enrolled for evaluating COX‐2 expression, 52.5% (38 of 73) were found to express COX‐2 in CTCs, and COX‐2 expression in CTCs was not found to associate with the clinicopathological factors. However, COX‐2 expression in mCTCs tended to have a higher rate in patients with metastasis compared with those without metastasis (72.0% vs 42.8%; P = 0.072). Furthermore, COX‐2 expression and mCTC marker expression correlated positively ( R = 0.287; P = 0.017). Further studies are required to investigate the clinical value of the expression of COX‐2 in mCTCs, especially in CRC patients with the advanced tumor stage and distant metastasis.

Downregulation of phosphorylated MKK4 is associated with a poor prognosis in colorectal cancer patients

Mitogen-activated protein kinase kinase 4 (MKK4) is a key mediator of Jun N-terminal kinase signaling and influences malignant metastasis. Here, we used immunohistochemistry to assess phosphorylated MMK4 (pMKK4) levels and examine their association with the clinicopathological features of a pilot set of patient samples consisting of normal colonic mucosa (NCM), colorectal adenoma (CA), and colorectal cancer (CRC) tissues. pMKK4 levels were also assessed in a validation set of CRC cases with accompanying follow-up data to confirm their clinicopathological and prognostic significance. pMKK4 levels, which were high in 79.17% of NCM samples, were downregulated in 33.33% of CA and 63.54% of CRC samples. pMKK4 downregulation was associated with metastasis, especially to the liver. In the validation set, pMKK4 downregulation was associated with increases in invasive depth, lymph node metastasis, distant metastasis, and TNM stage. Univariate analysis indicated that pMKK4 score, tumor differentiation, and TNM stage were correlated with disease-free survival and overall survival. Multivariate analysis indicated that decreased pMKK4 expression was an independent risk factor for disease-free survival in CRC patients. These results suggest that CRC patients with low pMKK4 immunochemistry scores should be monitored carefully for early detection of possible recurrences, especially liver metastasis.