Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers

Oikawa, Tsunekazu; Kamiya, Akihide; Zeniya, Mikio; Chikada, Hiromi; Hyuck, Ahn Dong; Yamazaki, Y.; Wauthier, Eliane; Tajiri, Hisao; Miller, Lance D.; Wang, Xin Wei; Reíd, Lola M.; Nakauchi, Hiromitsu

doi:10.1002/hep.26159

Cited by 176 publications

(199 citation statements)

References 51 publications

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“…Consistently, our data indicated a positive correlation between SALL4, AFP, and EPCAM expression in two independent HCC cohorts. Strikingly, SALL4 was recently shown to be expressed in a subset of human liver cancers with poor prognoses, while modification of SALL4 expression resulted in the alteration of cell proliferation in vitro and tumor growth in vivo, consistent with our current study [35]. A recent study reported the expression of SALL4 in 46% of HCC cases, which is almost comparable to our present study [36].…”

Section: Discussionsupporting

confidence: 92%

The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma

Zeng¹,

Yamashita²,

Kondo³

et al. 2014

Journal of Hepatology

130

120

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Background & Aims: Recent evidence suggests that hepatocellular carcinoma can be classified into certain molecular subtypes with distinct prognoses based on the stem/maturational status of the tumor. We investigated the transcription program deregulated in hepatocellular carcinomas with stem cell features. Methods: Gene and protein expression profiles were obtained from 238 (analyzed by microarray), 144 (analyzed by immunohistochemistry), and 61 (analyzed by qRT-PCR) hepatocellular carcinoma cases. Activation/suppression of an identified transcription factor was used to evaluate its role in cell lines. The relationship of the transcription factor and prognosis was statistically examined. Results: The transcription factor SALL4, known to regulate stemness in embryonic and hematopoietic stem cells, was found to be activated in a hepatocellular carcinoma subtype with stem cell features. SALL4-positive hepatocellular carcinoma patients were associated with high values of serum alpha fetoprotein, high frequency of hepatitis B virus infection, and poor prognosis after surgery compared with SALL4-negative patients. Activation of SALL4 enhanced spheroid formation and invasion capacities, key characteristics of cancer stem cells, and up-regulated the hepatic stem cell markers KRT19, EPCAM, and CD44 in cell lines. Knockdown of SALL4 resulted in the down-regulation of these stem cell markers, together with attenuation of the invasion capacity. The SALL4 expression status was associated with histone deacetylase activity in cell lines, and the histone deacetylase inhibitor successfully suppressed proliferation of SALL4-positive hepatocellular carcinoma cells. Conclusions: SALL4 is a valuable biomarker and therapeutic target for the diagnosis and treatment of hepatocellular carcinoma with stem cell features. Ó

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Section: Discussionsupporting

confidence: 92%

The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma

Zeng¹,

Yamashita²,

Kondo³

et al. 2014

Journal of Hepatology

130

120

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“…47 Although a germ cell marker, SALL-4, an oncofetal gene, has also been seen in HCC and considered as a marker of aggressiveness by virtue of its stem cell properties. [48][49][50] …”

Section: Immunohistochemistrymentioning

confidence: 99%

Tissue Diagnosis of Hepatocellular Carcinoma

Jain

2014

Journal of Clinical and Experimental Hepatology

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The current American Association for the Study of Liver Diseases (AASLD) guideline provides strategies for achieving the diagnosis of hepatocellular carcinoma (HCC) based on the size of liver nodules seen on surveillance imaging. For lesions less than 1 cm in size, follow-up surveillance imaging is recommended. Lesions larger than 2 cm require typical radiological hallmark on dynamic imaging. Lesions of 1-2 cm in size require typical imaging features including intense uptake of contrast during arterial phases followed by decreased enhancement during portal venous phases on at least 2 imaging modalities. In cases of atypical radiological features of the suspected lesion, tissue diagnosis either by fine needle aspiration or biopsy should be obtained. Although fine needle aspiration could give a smaller risk of seeding than biopsy, biopsy has been preferred over cytology. Percutaneous biopsy of HCC carries a potential risk of tumor seeding along the needle tract. However the risk is low and there is no clear evidence of post transplant recurrence due to needle tract seeding. Histopathologic assessment can differentiate between premalignant lesions such as dysplastic nodules and early HCC. Atypical variants of HCC can be recognized morphologically which may have associated prognostic value. ( J CLIN EXP HEPATOL 2014;4:S67-S73) H epatocellular carcinoma (HCC) is the sixth most common cancer in the world. 1 Its incidence is expected to rise in the future due to anticipated increase in cirrhosis secondary to viral hepatitis. Over the past 2 decades, the incidence of HCC has tripled, and hepatitis C virus (HCV) related HCC is the fastest-rising cause of cancer-related death in the United States. [2][3][4] Hepatocellular carcinoma develops within an established background of chronic liver disease in 70-90% of all patients. 5 The most frequent risk factor for HCC is chronic hepatitis B virus (HBV) infection in Asia and Africa. However HCV predominates as a risk factor in Europe and Japan. 2 Other well established risk factors are alcoholism, non-alcoholic fatty liver disease and diabetes. [6][7][8] Treatment depends on early diagnosis by screening high-risk patients when HCC is small and remains localized to the liver. Various studies suggest surveillance of HCC in cirrhotic patients irrespective of its etiology. Surveillance of non-cirrhotic patients is also advocated, especially in HBV carriers with serum viral load >10,000 copies/ml 9 or HCV infected patients with bridging fibrosis. Patients with HCV infection and advanced fibrosis remain at risk for HCC even after achieving sustained virological response following antiviral treatment.The preferred imaging method for screening is ultrasonography (USG) which is well tolerated and widely available. However, the sensitivity of USG for HCC detection is low because small nodules can be missed in a cirrhotic liver. 10 Use of contrast-enhanced USG improves the diagnostic performance of USG for HCC.The most used serological test in clinical setting for screening is alpha-fetop...

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“…It has been reported by three independent groups that SALL4 is a biomarker of HCCs with stem-like gene expression signatures and a poor prognosis [18,25,26]. SALL4 was recently found to directly interact with the epigenetic modulator nucleosome remodeling and histone deacetylase (NuRD) complex [27], thereby altering the histone modifications associated with stemness.…”

Section: Introductionmentioning

confidence: 99%

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

Nio

Yamashita

Okada

et al. 2015

Journal of Hepatology

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Background & Aims: Hepatocellular carcinoma is composed of a subset of cells with enhanced tumorigenicity and chemoresistance that are called cancer stem (or stem-like) cells. We explored the role of chromodomain-helicase-DNA-binding protein 4, which is encoded by the CHD4 gene and is known to epigenetically control gene regulation and DNA damage responses in EpCAM + liver cancer stem cells. Methods: Gene and protein expression profiles were determined by microarray and immunohistochemistry in 245 and 144 hepatocellular carcinoma patients, respectively. The relationship between gene/protein expression and prognosis was examined. The functional role of CHD4 was evaluated in primary hepatocellular carcinoma cells and in cell lines in vitro and in vivo. Results: CHD4 was abundantly expressed in EpCAM + hepatocellular carcinoma with expression of hepatic stem cell markers and poor prognosis in two independent cohorts. In cell lines, CHD4 knockdown increased chemosensitivity and CHD4 overexpression induced epirubicin chemoresistance. To inhibit the functions of CHD4 that are mediated through histone deacetylase and poly (ADP-ribose) polymerase, we evaluated the effect of the histone deacetylase inhibitor suberohydroxamic acid and the poly (ADP-ribose) polymerase inhibitor AG-014699. Treatment with either suberohydroxamic acid or AG-014699 reduced the number of EpCAM + liver cancer stem cells in vitro, and suberohydroxamic acid and AG-014699 in combination successfully inhibited tumor growth in a mouse xenograft model.Conclusions: CHD4 plays a pivotal role in chemoresistance and the maintenance of stemness in liver cancer stem cells and is therefore a good target for the eradication of hepatocellular carcinoma. Ó

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Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers

Cited by 176 publications

References 51 publications

The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma

The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma

Tissue Diagnosis of Hepatocellular Carcinoma

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

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