Hepatitis C Virus-Induced Cancer Stem Cell-Like Signatures in Cell Culture and Murine Tumor Xenografts

Ali, Naushad; Allam, Hisham; May, Randal; Sureban, Sripathi M.; Bronze, Michael S.; Bader, Ted; Umar, Shahid; Anant, Srikant; Houchen, Courtney W.

doi:10.1128/jvi.05920-11

Cited by 76 publications

(106 citation statements)

References 64 publications

(86 reference statements)

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“…A previous study revealed that hepatitis C virus replication was positively associated with DCLK1 expression (25). By contrast, siRNA knockdown of DCLK1 diminished hepatitis C virus replication and lowered the expression of EMT-promoting factors (21,25,26). Furthermore, DCLK1 served a crucial function in the development of cirrhosis and HCC following sustained hepatitis C virus infection (50).…”

Section: Discussionmentioning

confidence: 98%

“…HCC associated with infection with HBV has become one of the fastest-rising causes of cancer-associated mortality in China (2,51). Given the importance of DCLK1 inflammatory and oncogenic functions in virus-induced chronic diseases (25,31,50). the present study assessed the association between DCLK1 expression and hepatitis B virus and cirrhosis levels.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, previous studies have demonstrated DCLK1 expression in multiple types of solid tumor, including colon, intestinal and pancreatic cancer, and HCC (20,(25)(26)(27). In addition, it has been revealed that patients with a high (>4) DCLK1 staining score are associated with increased cancer-specific mortality rates compared with those with a low (0-4) DCLK1 staining score in colorectal neoplasia (27).…”

Section: Introductionmentioning

confidence: 98%

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Expression and prognostic significance of doublecortin‑like kinase 1 in patients with hepatocellular carcinoma

2017

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Abstract. Doublecortin-like kinase 1 (DCLK1), a putative cancer stem cell marker in intestinal and pancreatic tumors, is associated with tumor pathogenesis and progression, and poor survival outcomes in numerous types of cancer. However, DCLK1 expression and its prognostic value remain unclear in hepatocellular carcinoma (HCC). In the present study, the expression of DCLK1 was assessed using immunohistochemistry in 96 resected HCC and 68 adjacent tissue specimens. The staining intensity and the percentage of stained cells were scored on a scale of 0-3 and 0-4, respectively. Tissue was defined as positive for DCLK1 if the composite multiple score was >3. Cytoplasmic expression of DCLK1 was observed in HCC and adjacent tissue specimens with an expression rate of 81% (78/96) and 74% (50/68), respectively; the median score was 4.6 and 3.9, respectively, and no statistically significant difference was observed between HCC and adjacent tissues (P=0.087). DCLK1 expression was positively associated with intrahepatic metastasis (P=0.035). Furthermore, univariate analysis revealed that DCLK1 expression was significantly associated with poor disease-free survival (DFS) and overall survival (P=0.024 and 0.034). Multivariate analysis also demonstrated that DCLK1 expression was an independent prognostic factor for DFS in HCC (P=0.019; hazard ratio, 1.546; 95% confidence interval, 1.330-1.725). Stratified Kaplan-Meier survival curves revealed that DCLK1 expression predicted poorer DFS with respect to positivity for three characteristics: Portal venous metastasis, intrahepatic metastasis, and cirrhosis (P=0.020, P=0.007 and P=0.017, respectively). Collectively, the results of the present study suggested that DCLK1, functioning as a tumor promoter, is frequently overexpressed in HCC, and that DCLK1 expression is associated with poor DFS in patients with HCC. DCLK1 may represent a promising therapeutic target in HCC and requires further study.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Expression and prognostic significance of doublecortin‑like kinase 1 in patients with hepatocellular carcinoma

2017

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“…Several lines of evidence suggest that HCV infection is intimately linked to the presence of hepatic stem cells, such as Hepatic Progenitor Cells (HPCs) (Ali et al, 2011;Machida et al, 2012;Wu et al, 2012). HPCs are small periportal cells capable of proliferation and differentiation into both hepatocytes and bile ductular epithelium (Clouston et al, 2005;Roskams, 2003).…”

Section: Cancer Stem Cells 121 Potential Cancer Stem Cellsmentioning

confidence: 99%

“…Further, there is evidence that HCV infection directly induces HPCs and the presence of HPCs facilitates HCV replication. For example, HCV infection in vitro induces both cancer stem cell markers (DCAMKL-1, CK19, α-fetoprotein, active c-Src) and a distinct tumor phenotype (Ali et al, 2011); expression of HCV NS5A gene coupled with alcohol intake induces stem cell regulator Nanog expression through the TLR4 signaling pathway (Machida et al, 2012;. Finally, it has been shown that HCV can infect Differentiated Human Hepatocyte-like cells (DHHs) from human ESCs and induced Pluripotent Stem Cells (iPSCs) and clinical HCV isolates reportedly infect HPCs with a higher efficiency than infection of mature hepatocytes .…”

Section: Cancer Stem Cells 121 Potential Cancer Stem Cellsmentioning

confidence: 99%

Epigenetic Mechanisms in Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Potential New Link Between Stem Cells, Virology and Cancer

Feng¹

2013

American Medical Journal

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Recent studies suggest that epigenetic mechanisms are not only essential for the dynamic transcriptional regulation in embryonic and somatic stem cells, but are also actively involved in tumorigenesis: genes important for pluripotency are epigenetically regulated and aberrant epigenetic changes have been detected in virtually all human malignancies studied, including Hepatocellular Carcinoma (HCC). Infection with Hepatitis C Virus (HCV) is a major risk factor for the development of HCC. Despite the fact that HCV is a RNA virus without a DNA intermediate, recent studies demonstrate that HCV viral proteins may actively participate in epigenetic regulation of hepatic cancer stem cell phenotypes and induce HCC-specific epigenetic changes. Identification of host epigenetic alterations induced by HCV infection and epigenetic differences between hepatic cancer stem cells and the bulk non-tumorigenic cancer cells, may yield potential biomarkers for early detection, as well as therapeutic targets for HCV associated HCC.

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Conducting scaffolds for liver tissue engineering

Rad

Ali

Kotturi

et al. 2014

J. Biomed. Mater. Res.

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It is known that there is a correlation between a cell membrane potential and the proliferation of the cell. The high proliferation capacity of liver cells can also be attributed to its specific cell membrane potential as liver cell is recognized as one of the most depolarized of all differentiated cells. We hypothesized that this phenomenon can be emphasized by growing liver cells in conducting scaffolds that can increase the electrical communication among the cells. In this article, using tissue engineering techniques, we grew hepatocyte cells in scaffolds with various compositions. It was found that the scaffolds containing conducting polymer of poly (3,4-ethylenedioxythiophene) (PEDOT) provide the best condition for attachment and proliferation of the cells. More specifically, the blend of hyaluronan, PEDOT, and collagen (I) as dopants in gelatin-chitosan-based scaffold presented the best cell/scaffold interactions for regeneration of liver cells.

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Hepatitis C Virus-Induced Cancer Stem Cell-Like Signatures in Cell Culture and Murine Tumor Xenografts

Abstract: Hepatitis C virus (HCV) infection is a prominent risk factor for the development of hepatocellular carcinoma (HCC).

Cited by 76 publications

References 64 publications

Expression and prognostic significance of doublecortin‑like kinase 1 in patients with hepatocellular carcinoma

Expression and prognostic significance of doublecortin‑like kinase 1 in patients with hepatocellular carcinoma

Epigenetic Mechanisms in Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Potential New Link Between Stem Cells, Virology and Cancer

Conducting scaffolds for liver tissue engineering

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