Loss of ATOH8 Increases Stem Cell Features of Hepatocellular Carcinoma Cells

Song, Yangyang; Pan, Guangjin; Chen, Leilei; Ma, Stephanie; Zeng, Tingting; Chan, Tim; Li, Lei; Lian, Qizhou; Chow, Raymond Kwok Kei; Cai, Xiujuan; Li, Yan; Liu, Ming; Li, Yun; Zhu, Ying–Hui; Wong, Nathalie; Yuan, Yufeng; Pei, Duanqing; Guan, Xin‐Yuan

doi:10.1053/j.gastro.2015.06.010

Cited by 48 publications

(53 citation statements)

References 42 publications

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“…The p value approached significance, but the small patient numbers limited the comparison. To our knowledge, this has not been previously reported, although ALKP has been noted to be an HCC prognostic factor in general [37,38,39] and a marker for stem cells, including HCC stem cells [40]. Thus, serum ALKP levels may contribute to patient care decision-making in the setting of metastasis.…”

Section: Discussionmentioning

confidence: 77%

“…They were treated with cisplatin-based chemoembolization as has been our practice [23,24]. Almost all patients presented with the huge bulk of their disease within the liver, which needed to be treated to prevent or minimize symptoms and tumor-associated liver failure [40]. It is our experience, not analyzed in this retrospective study, that HCC patient deaths are nearly always liver-related and rarely from metastasis [41].…”

Section: Discussionmentioning

confidence: 99%

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Hepatocellular Carcinoma Extrahepatic Metastasis in Relation to Tumor Size and Alkaline Phosphatase Levels

Carr

Guerra

2016

Oncology

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Background: Hepatocellular carcinoma (HCC) is known to metastasize. However, there are few reports on patients with metastasis at the time of HCC diagnosis. Aims: To evaluate the incidence and characteristics of extrahepatic metastasis patients presenting at baseline with noncurable, advanced HCC. Results: The total HCC cohort was initially dichotomized into 2 subcohorts, with (n = 214) and without (n = 719) extrahepatic metastasis (‘metastasis'), and patient baseline characteristics were compared. The main findings for patients with metastasis (22.9% of total cohort) compared with other, nonmetastatic patients were: more advanced tumors, as judged by larger tumor diameters, more tumor multifocality and percent with portal vein thrombosis, higher blood α-fetoprotein and des γ-carboxy prothrombin levels and alkaline phosphatase (ALKP), but not bilirubin levels, and a lower incidence of cirrhosis. There was a strong correlation between increases in tumor size and percent of patients with metastasis. A subset of patients with larger tumors was identified with low blood ALKP levels and better survival. Survival in the total metastasis cohort was lower than in the non-metastasis cohort, as expected, but only in patients with smaller tumors. In patients with larger tumors, survival with or without metastasis was similar and poor. Conclusions: There was a lower incidence of cirrhosis in HCC patients with metastasis, and they had larger and more aggressive primary tumors. Patients with smaller, but not larger, tumors and metastasis had worse prognosis than patients without metastasis. A distinct subset of metastatic patients was identified that had better prognosis and low ALKP levels.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Hepatocellular Carcinoma Extrahepatic Metastasis in Relation to Tumor Size and Alkaline Phosphatase Levels

Carr

Guerra

2016

Oncology

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“…In addition, this study found the following tissue specific TFs that were not reported in breast cancer: ATOH8, DMRT2, TBX15 and ZNF367. Down-regulated ATOH8 has been proven to contribute to the malignant phenotype of nasopharyngeal carcinoma [29] and increases the stem cell features of hepatocellular carcinoma cells [30]. Tun et al reported that DMRT2 and other developmental TFs were significantly down-regulated in clear cell renal cell carcinoma [31].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive tissue-specific gene set enrichment analysis and transcription factor analysis of breast cancer by integrating 14 gene expression datasets

Tang

et al. 2016

Oncotarget

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Breast cancer is the most commonly diagnosed malignancy in women. Several key genes and pathways have been proven to correlate with breast cancer pathology. This study sought to explore the differences in key transcription factors (TFs), transcriptional regulation networks and dysregulated pathways in different tissues in breast cancer. We employed 14 breast cancer datasets from NCBI-GEO and performed an integrated analysis in three different tissues including breast, blood and saliva. The results showed that there were eight genes (CEBPD, EGR1, EGR2, EGR3, FOS, FOSB, ID1 and NFIL3) down-regulated in breast tissue but up-regulated in blood tissue. Furthermore, we identified several unreported tissue-specific TFs that may contribute to breast cancer, including ATOH8, DMRT2, TBX15 and ZNF367. The dysregulation of these TFs damaged lipid metabolism, development, cell adhesion, proliferation, differentiation and metastasis processes. Among these pathways, the breast tissue showed the most serious impairment and the blood tissue showed a relatively moderate damage, whereas the saliva tissue was almost unaffected. This study could be helpful for future biomarker discovery, drug design, and therapeutic and predictive applications in breast cancers.

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“…Huh7 (5x10 6 cells) with 95% viability were injected subcutaneously into the hind legs of 6-week-old BALB/c athymic nude mice (SLC Inc., Hamamatsu, Japan) [27, 28]. When tumors reached a volume of 200–250 mm 3 , mice were randomly allocated to four groups as follows: (1) the tumor control group, (2) the SASP group (5 mg/20 g, 9 days) [22], (3) the IR group (5Gy), and (4) the SASP plus IR group.…”

Section: Methodsmentioning

confidence: 99%

Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells

Song

Jang

Shin

et al. 2017

J Exp Clin Cancer Res

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BackgroundCD133-positive cells in hepatocellular carcinoma (HCC) exhibit cancer stem cell (CSC)-like properties as well as resistance to chemotherapeutic agents and ionizing radiation; however, their function remains unknown. In this paper, we identified a hitherto unknown mechanism to overcome CD133-induced resistance to anticancer therapy.MethodsWe applied an alternative approach to enrich the CD133-positive HCC population by manipulating 3D culture conditions. Defense mechanisms against reactive oxygen species (ROS) in CSC spheroids were evaluated by fluorescence image-based phenotypic screening system. Further, we studied the effect of sulfasalazine on ROS defense system and synergistic therapeutic efficacy of anticancer therapies both in culture and in vivo HCC xenograft mouse model.ResultsHere, we found that oxidative stress increase CD133 expression in HCC and increased CD133 expression enhanced the capacity of the defense system against ROS, and thereby play a central role in resistance to liver cancer therapy. Moreover, ablation of CD133 attenuated not only the capacity for defense against ROS, but also chemoresistance, in HCC through decreasing glutathione (GSH) levels in vitro. Sulfasalazine, a potent xCT inhibitor that plays an important role in maintaining GSH levels, impaired the ROS defense system and increased the therapeutic efficacy of anticancer therapies in CD133-positive HCC but not CD133-negative HCC in vivo and in vitro.ConclusionThese results strongly indicate functional roles for CD133 in ROS defense and in evading anticancer therapies in HCC, and suggest that sulfasalazine, administered in combination with conventional chemotherapy, might be an effective strategy against CD133-positive HCC cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0511-7) contains supplementary material, which is available to authorized users.

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Loss of ATOH8 Increases Stem Cell Features of Hepatocellular Carcinoma Cells

Cited by 48 publications

References 42 publications

Hepatocellular Carcinoma Extrahepatic Metastasis in Relation to Tumor Size and Alkaline Phosphatase Levels

Hepatocellular Carcinoma Extrahepatic Metastasis in Relation to Tumor Size and Alkaline Phosphatase Levels

Comprehensive tissue-specific gene set enrichment analysis and transcription factor analysis of breast cancer by integrating 14 gene expression datasets

Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells

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