Down‐regulation of microRNA‐26a (miR‐26a) is associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the ...roles of miR‐26a in tumor growth and metastasis of HCC and found that miR‐26a was frequently down‐regulated in HCC tissues. Down‐regulation of miR‐26a correlated with HCC recurrence and metastasis. Through gain‐ and loss‐of‐function studies, miR‐26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR‐26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR‐26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin‐6 (IL‐6) was identified as a target of miR‐26a. Knockdown of IL‐6 induced effects on HCC cells similar to those induced by miR‐26a. In contrast, IL‐6 treatment abrogated the effects induced by miR‐26a up‐regulation. Moreover, miR‐26a dramatically suppressed expression of signal transducer and activator of transcription 3 (Stat3) target genes, including Bcl‐2, Mcl‐1, cyclin D1, and MMP2. IL‐6 treatment antagonized this effect, while knockdown of IL‐6 by IL‐6 short hairpin RNA (shIL‐6) induced inhibitory effects on the expression of p‐Stat3 and its main target genes, similar to miR‐26a. The messenger RNA and protein levels of IL‐6 inversely correlated with miR‐26a in HCCs. Patients with high miR‐26a or low IL‐6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR‐26a, IL‐6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Conclusion: miR‐26a could suppress tumor growth and metastasis of HCC through IL‐6‐Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC. (HEPATOLOGY 2013)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To assess the effects of cetuximab plus chemotherapy as first-line treatment for unresectable colorectal liver metastases (CLMs).
After resection of their primary tumors, patients with KRAS wild-type ...synchronous nonresectable liver-limited metastases from colorectal cancer were randomly assigned to receive chemotherapy (FOLFIRI fluorouracil, leucovorin, and irinotecan or mFOLFOX6 modified fluorouracil, leucovorin, and oxaliplatin) plus cetuximab (arm A) or chemotherapy alone (arm B). The primary end point was the rate of patients converted to resection for liver metastases. Secondary end points included tumor response and survival.
The intent-to-treat population comprised 138 patients; 70 patients were randomly assigned to arm A and 68 to arm B. After a median of 25.0 months of follow-up, the 3-year overall survival (OS) rate and median survival time (MST) for all patients were 30% and 24.4 months, respectively. The R0 resection rates for liver metastases were 25.7% (18 of 70 patients) in arm A and 7.4% (five of 68 patients) in arm B, which were significantly different (P < .01). Patients in arm A had improved objective response rates (57.1% v 29.4%; P < .01), increased 3-year OS rate (41% v 18%; P = .013) and prolonged MST (30.9 v 21.0 months; P = .013) compared with those in arm B. In addition, in arm A, patients who had resection of liver metastases had a significantly improved MST (46.4 v 25.7 months; P < .01) compared with those who did not undergo surgery.
For patients with initially unresectable KRAS wild-type CLMs, cetuximab combined with chemotherapy improved the resectability of liver metastases and improved response rates and survival compared with chemotherapy alone.
Globally, hepatocellular carcinoma (HCC) accounts for 70%‐85% of primary liver cancers and ranks as the second leading cause of male cancer death. Serum alpha‐fetoprotein (AFP), normally highly ...expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP− tumors differ biologically. Multivariable analysis in 237 HCC cases demonstrates that AFP level predicts poor survival independent of tumor stage (P < 0.043). Using microarray‐based global microRNA (miRNA) profiling, we found that miRNA‐29 (miR‐29) family members were the most significantly (P < 0.001) down‐regulated miRNAs in AFP+ tumors. Consistent with miR‐29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (P < 0.001) between miR‐29 and DNMT3A gene expression, suggesting that they might be functionally antagonistic. Moreover, global DNA methylation profiling reveals that AFP+ and AFP− HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Experimentally, we found that AFP expression in AFP− HCC cells induces cell proliferation, migration, and invasion. Overexpression of AFP, or conditioned media from AFP+ cells, inhibits miR‐29a expression and induces DNMT3A expression in AFP− HCC cells. AFP also inhibited transcription of the miR‐29a/b‐1 locus, and this effect is mediated through c‐MYC binding to the transcript of miR‐29a/b‐1. Furthermore, AFP expression promotes tumor growth of AFP− HCC cells in nude mice. Conclusion: Tumor biology differs considerably between AFP+ HCC and AFP− HCC; AFP is a functional antagonist of miR‐29, which may contribute to global epigenetic alterations and poor prognosis in HCC. (Hepatology 2014;60:872–883)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The effects of mesenchymal stem cells (MSC) on the growth and metastasis of human malignancies including hepatocellular carcinoma (HCC) are controversial, and the underlying mechanisms are not yet ...understood. The aim of this study was to explore the role of MSC in the progression of HCC. We investigated the effect of MSC on in vitro proliferation and invasion and in vivo tumor growth and pulmonary metastasis of MHCC97‐H HCC cells with a high metastatic potential. The mRNA and protein levels of transforming growth factor‐beta 1 (TGFβ1) and MMP, and their association with the effects of MSC on HCC cells were also evaluated. Co‐culture of MHCC97‐H cells with MSC conditioned medium significantly enhanced in vitro proliferation but inhibited invasiveness. Following MSC treatment of a nude mouse model bearing human HCC, the MSC were predominantly located in the HCC tissues. Compared with controls, MSC‐treated mice exhibited significantly larger tumors (3080.51 ± 1234.78 mm3vs 2223.75 ± 1000.60 mm3, P = 0.045), but decreased cellular numbers of lung metastases (49.75 ± 18.86 vs 227.22 ± 74.67, P = 0.046). Expression of TGFβ1 and MMP‐2 was significantly downregulated in the MSC‐treated HCC cells. TGFβ siRNA concurrently downregulated expression of TGFβ and MMP‐2 in HCC cells and blocked the MSC‐induced proliferation and invasiveness of MHCC97‐H cells. The MSC enhanced tumor growth but significantly inhibited the invasiveness and metastasis of HCC, possibly through downregulation of TGFβ1. These findings suggest that MSC could be useful in controlling metastatic recurrence of HCC. (Cancer Sci 2010; 101: 2546–2553)
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MicroRNAs (miRNAs) have been used as cancer‐related biomarkers. Hepatocellular carcinoma (HCC) is an aggressive cancer with a dismal outcome largely due to metastasis and postsurgical recurrence. We ...investigated whether the expression of certain miRNAs are associated with HCC metastasis. We examined the miRNA expression profiles of 482 cancerous and noncancerous specimens from radical resection of 241 patients with HCC. Using a supervised algorithm and a clinically well‐defined cohort of 131 cases, we built a unique 20‐miRNA metastasis signature that could significantly predict (P < 0.001) primary HCC tissues with venous metastases from metastasis‐free solitary tumors with 10‐fold cross‐validation. However, significant miRNAs could not be identified from the corresponding noncancerous hepatic tissues. A survival risk prediction analysis revealed that a majority of the metastasis‐related miRNAs were associated with survival. Furthermore, the 20‐miRNA tumor signature was validated in 110 additional cases as a significant independent predictor of survival (P = 0.009) and was significantly associated with both survival and relapse in 89 cases of early stage HCC (P = 0.022 and 0.002, respectively). These 20 miRNAs may provide a simple profiling method to assist in identifying patients with HCC who are likely to develop metastases/recurrence. In addition, functional analysis of these miRNAs may enhance our biological understanding of HCC metastasis. (HEPATOLOGY 2008.)
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Probiotics are considered to be a potential treatment for ulcerative colitis (UC). The aim of this study was to compare the preventive effect of a space flight‐induced mutant L. reuteri F‐9‐35 and ...its wild type on UC in vivo. Female mice were randomly assigned to five groups: one normal and four colitic. Mice from colitis groups were daily gavaged with 0.2 mL 12% (w/v) skim milk containing the mutant or wild type (1 × 1011 CFU/mL), skim milk alone or distilled water for the whole experiment period, starting 7 days before colitis induction. UC was induced by administrating mice with 3.5% (w/v) dextran sulfate sodium (DSS) in drinking water for 7 days, after which DSS was removed and maintained for 3 days as a recovery phase. The results showed that the mice fed with L. reuteri F‐9‐35 had less inflammatory phenotype according to macroscopic and histological analysis, reduced myeloperoxidase activity, and lower expression of proinflammatory genes (Tumor necrosis factor‐α, cyclooxygenase‐2 and interleukin‐6) in colonic tissue compared with control. Furthermore, L. reuteri F‐9‐35 protected the mice from gut microbiota dysbiosis from DDS induced colitis. Neither wild type nor the milk alone had such beneficial effects. From above we conclude that L. reuteri F‐9‐35 has great potential in the prevention of UC as a dietary supplement.
Practical Application
Ulcerative colitis (UC) is the most common inflammatory bowel diseases and there is still a lack of safe and effective treatments. Consumption of L. reuteri F‐9‐35 may effective in preventing human UC.
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Metastasis-related recurrence often occurs in hepatocellular carcinoma (HCC) patients who receive curative therapies. At present, it is challenging to identify patients with high risk of recurrence, ...which would warrant additional therapies. In this study, we sought to analyze a recently developed metastasis-related gene signature for its utility in predicting HCC survival, using 2 independent cohorts consisting of a total of 386 patients who received radical resection. Cohort 1 contained 247 predominantly HBV-positive cases analyzed with an Affymetrix platform, whereas cohort 2 contained 139 cases with mixed etiology analyzed with the NCI Oligo Set microarray platform. We employed a survival risk prediction algorithm with training, test, and independent cross-validation strategies and found that the gene signature is predictive of overall and disease-free survival. Importantly, risk was significantly predicted independently of clinical characteristics and microarray platform. In addition, survival prediction was successful in patients with early disease, such as small (<5 cm in diameter) and solitary tumors, and the signature predicted particularly well for early recurrence risk (<2 years), especially when combined with serum alpha fetoprotein or tumor staging. In conclusion, we have shown in 2 independent cohorts with mixed etiologies and ethnicity that the metastasis gene signature is a useful tool to predict HCC outcome, suggesting the general utility of this classifier. We recommend the use of this classifier as a molecular diagnostic test to assess the risk that an HCC patient will develop tumor relapse within 2 years after surgical resection, particularly for those with early-stage tumors and solitary presentation.
MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate gene expression with functional links to tumorigenesis. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, ...and it is heterogeneous in clinical outcomes and biological activities. Recently, we have identified a subset of highly invasive epithelial cell adhesion molecule (EpCAM)+ HCC cells from alpha‐fetoprotein (AFP)+ tumors with cancer stem/progenitor cell features, that is, the abilities to self‐renew, differentiate, and initiate aggressive tumors in vivo. Here, using a global microarray‐based miRNA profiling approach followed by validation with quantitative reverse transcription polymerase chain reaction, we have demonstrated that conserved miR‐181 family members were up‐regulated in EpCAM+AFP+ HCCs and in EpCAM+ HCC cells isolated from AFP+ tumors. Moreover, miR‐181 family members were highly expressed in embryonic livers and in isolated hepatic stem cells. Importantly, inhibition of miR‐181 led to a reduction in EpCAM+ HCC cell quantity and tumor initiating ability, whereas exogenous miR‐181 expression in HCC cells resulted in an enrichment of EpCAM+ HCC cells. We have found that miR‐181 could directly target hepatic transcriptional regulators of differentiation (for example, caudal type homeobox transcription factor 2 CDX2 and GATA binding protein 6 GATA6) and an inhibitor of Wnt/β‐catenin signaling (nemo‐like kinase NLK). Taken together, our results define a novel regulatory link between miR‐181s and human EpCAM+ liver cancer stem/progenitor cells and imply that molecular targeting of miR‐181 may eradicate HCC. (HEPATOLOGY 2009.)
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Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this ...study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix messenger RNA (mRNA) and NanoString microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in an additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC‐specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC‐specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR‐200c signaling to epithelial‐mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR‐200c resulted in an induction of EMT, whereas activation of miR‐200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR‐200c and neural cell adhesion molecule 1 (NCAM1) expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR‐200c. Conclusion: Our results indicate that ICC and HCC share common stem‐like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell‐like ICC. (HEPATOLOGY 2012;56:1792–1803)
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MicroRNA (miR)‐26a can suppress tumor growth and metastasis of hepatocellular carcinoma (HCC). Since angiogenesis is important for tumor growth and metastasis, we investigated the possible roles of ...miR‐26a in tumor angiogenesis. Down‐regulation of miR‐26a was found to correlate with an increased angiogenic potential of HCC. Through gain‐ and loss‐of‐function studies, miR‐26a was demonstrated to significantly inhibit vascular endothelial growth factor A (VEGFA) expression in HCC cells and then suppress the promoting effects of HCC cells on in vitro proliferation, migration, and capillary tube formation of endothelial cells, as well as in vivo tumor angiogenesis of HCC. Hepatocyte growth factor (HGF) was identified as a target of miR‐26a. HGF simulation antagonized the effects induced by miR‐26a up‐regulation. In contrast, silencing HGF induced similar effects to miR‐26a. We further found that miR‐26a exerted its antiangiogenesis function, at least in part, by inhibiting HGF‐hepatocyte growth factor receptor (cMet) and its downstream signaling pathway, in turn, suppressing VEGFA production in HCC cells and impairing VEGFR2‐signaling in endothelial cells. HCC patients who had high miR‐26a, low HGF, low VEGFA, or low microvessel density (MVD) in tumor tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR‐26a, or in combination with HGF, was demonstrated to be an independent prognostic indicator for OS and TTR of HCC patients. Conclusion: miR‐26a could suppress tumor angiogenesis of HCC through HGF‐cMet signaling, and it is a new hopeful therapeutic target and prognostic marker for HCC. (Hepatology 2014;59:1874–1885)
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