Suppression of SAMSN1 Expression is Associated with the Malignant Phenotype of Hepatocellular Carcinoma

Sueoka, Satoshi; Kanda, Mitsuro; Sugimoto, Hiroyuki; Shimizu, Dai; Nomoto, Shuji; Oya, Hisaharu; Takami, Hideki; Ezaka, Kazuhiro; Hashimoto, R; Tanaka, Yuri; Okamura, Yukiyasu; Yamada, Suguru; Fujii, Tsutomu; Nakayama, Goro; Koike, Masahiko; Fujiwara, Michitaka; Kodera, Yasuhiro

doi:10.1245/s10434-015-4524-1

Cited by 20 publications

(25 citation statements)

References 41 publications

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“…SAMSN1 regulates HDAC1 activity and is known as a tumor suppressor in multiple myeloma [ 44 , 45 ]. Its downregulation is related to a poor prognosis in gastric cancer and hepatocellular carcinoma patients [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors

Kramer

Moreno

Frühwald

et al. 2017

IJMS

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Rhabdoid tumors (RT) are malignant neoplasms of early childhood. Despite intensive therapy, survival is poor and new treatment approaches are required. The only recurrent mutations in these tumors affect SMARCB1 and less commonly SMARCA4, both subunits of the chromatin remodeling complex SWItch/Sucrose Non-Fermentable (SWI/SNF). Loss of these two core subunits alters the function of the SWI/SNF complex, resulting in tumor development. We hypothesized that inhibition of aberrant SWI/SNF function by selective blockade of the BRD9 subunit of the SWI/SNF complex would reduce tumor cell proliferation. The cytotoxic and anti-proliferative effects of two specific chemical probes (I-BRD9 and BI-9564) which target the bromodomain of SWI/SNF protein BRD9 were evaluated in 5 RT cell lines. Combinatorial effects of I-BRD9 and cytotoxic drugs on cell proliferation were evaluated by cytotoxicity assays. Single compound treatment of RT cells with I-BRD9 and BI-9564 resulted in decreased cell proliferation, G1-arrest and apoptosis. Combined treatment of doxorubicin or carboplatin with I-BRD9 resulted in additive to synergistic inhibitory effects on cell proliferation. In contrast, the combination of I-BRD9 with vincristine demonstrated the antagonistic effects of these two compounds. We conclude that the BRD9 bromodomain is an attractive target for novel therapies in this cancer.

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Section: Discussionmentioning

confidence: 99%

BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors

Kramer

Moreno

Frühwald

et al. 2017

IJMS

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“…For example, patients with an earlier tumor stage sometimes have unfavorable prognosis. Extrahepatic recurrences, such as lung, bone, and brain metastases, can be a cause of an unexpected and rapidly deteriorating patient course; however, no methods for predicting the likelihood of extrahepatic recurrences of HCC are currently available [ 8 , 9 ]. Conversely, some patients are long-term survivors after resection of advanced HCC without adjuvant therapy.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of GPR155 as a prognostic factor after curative resection of hepatocellular carcinoma

et al. 2017

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BackgroundMolecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC). In this study, we focused on G protein-coupled receptor 155 (GPR155), a cell surface signaling protein, as a candidate biomarker.MethodsWe analyzed GPR155 expression, DNA methylation, and copy number in HCC cell lines. The clinical significance of GPR155 expression was evaluated using 144 pairs of surgically resected liver and normal tissues with subgroup analysis based on hepatitis virus infection.Results GPR155 mRNA expression levels were differential and were decreased in 89% of HCC cell lines. No DNA methylation was detected, whereas copy number alterations were present in five (56%) HCC cell lines. GPR155 mRNA expression level was independent of background liver status and significantly lower in HCC tissues than corresponding normal liver tissues. The expression patterns of GPR155 protein by immunohistochemical staining were significantly associated with those of GPR155 mRNA. Downregulation of GPR155 was significantly associated with more aggressive HCC phenotypes including high preoperative α-fetoprotein, poor differentiation, serosal infiltration, vascular invasion, and advanced disease stage. Patients with downregulation of GPR155 were more likely to have worse prognosis after curative resection irrespective of hepatitis virus infection. Patients who experienced extrahepatic (distant) recurrences had significantly lower GPR155 expression than those with intrahepatic (liver confined) recurrences.ConclusionsDownregulation of GPR155 may serve as a prognosticator that also predicts initial recurrence sites independent of hepatitis virus infection.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3629-2) contains supplementary material, which is available to authorized users.

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“…Further examinations will be required to translate results of the present study to the clinic and to determine how best to use the expression panel. Indeed, the single use of our 12 candidate markers showed modest predictive performance as well as AFP or PIVKA-II, which are currently used as tumor markers in HCC [ 19 , 22 , 23 ]. However, our integrated multigene expression panel enables physicians to easily identify individuals expected to have an excellent prognosis (low risk), and conversely those expected to have a dismal prognosis (high risk) immediately after surgery.…”

Section: Discussionmentioning

confidence: 99%

An integrated multigene expression panel to predict long-term survival after curative hepatectomy in patients with hepatocellular carcinoma

et al. 2017

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Hepatocellular carcinoma (HCC) frequently recurs even after curative hepatectomy. To develop an integrated multigene expression panel, 144 patients were randomly assigned to either discovery or validation set in a 1:2 ratio. Using surgically resected HCC specimens, expression levels of 12 candidate molecular markers were determined using quantitative reverse-transcriptase PCR. In the discovery set, an expression panel was developed according to the concordance index (C-index) values for overall survival from all 4095 combinations of the 12 candidate molecular markers. Expression scores was determined with weighting according to the coefficient in a Cox regression, and patients were classified into grade 1, 2 and 3. Reproducibility was then tested in the validation set. A panel consisting of four markers, PRMT5, MAGED4, DPYSL3 and AJAP1 was selected as the optimal and most well-balanced set with a C-index value of 0.707. Patient prognosis was clearly stratified by the expression grade using this panel. In the validation set, both overall and disease-free survival rates decreased incrementally with as the grade increased. Higher grades were significantly associated with tumor multiplicity and vessel invasion. The prevalence of extrahepatic recurrences was increased in grade 3 patients. The integrated multigene expression panel clearly stratified HCC patients into low, intermediate and high risk.

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Suppression of SAMSN1 Expression is Associated with the Malignant Phenotype of Hepatocellular Carcinoma

Abstract: Our findings indicate that inhibition of SAMSN1 transcription through DNA hypermethylation may influence the progression of HCC and thus represent a novel biomarker of the phenotype of HCC cells.

Cited by 20 publications

References 41 publications

BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors

BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors

Downregulation of GPR155 as a prognostic factor after curative resection of hepatocellular carcinoma

An integrated multigene expression panel to predict long-term survival after curative hepatectomy in patients with hepatocellular carcinoma

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