• Asian Pacific Journal of Cancer Prevention
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• 제14권2호
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• pp.747-752
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• 2013

Oncostatin M (OSM) is a multifunctional cellular regulator acting on a wide variety of cells, which has potential roles in the regulation of gene activation, cell survival, proliferation and differentiation. Previous studies have shown that OSM can induce morphological and/or functional differentiation and maturation of many tumor cells. However, the action of OSM on the induction of differentiation of human hepatocellular carcinoma (HCC) has not been reported. Here, we investigated the effects of different concentrations of OSM on human HCC cell line SMMC-7721 growth, proliferation, cell cycling, apoptosis and differentiation in vitro. Cell growth was determined via MTT assay, proliferation by cell cycle analysis, apoptosis by flow cytometry, morphology by transmission electronic microscopy, and cell function by detection of biochemical markers. Our results demonstrated that OSM strongly inhibited the growth of SMMC-7721 cells in a dose-dependent manner, associated with decreased clonogenicity. Cell cycle analysis revealed a decreased proportion of cells in S phase, with arrest at G0/G1. The apotosis rate was increased after OSM treatment compared to the control. These changes were associated with striking changes in cellular morphology, toward a more mature hepatic phenotype, accompanied by significant reduction of the expression of AFP and specific activity of ${\gamma}$-GT, with remarkable increase in secretion of albumin and ALP activity. Taken together, our findings indicate that OSM could induce the differentiation and reduce cell viability of SMMC-7721 cells, suggesting that differentiation therapy with OSM offers the opportunity for therapeutic intervention in HCC.

• Nuclear Medicine and Molecular Imaging
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• 제42권5호
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• pp.414-418
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• 2008

간암의 정맥계 침범은 흔하나 심장 침범은 드물고 예후가 불량할 뿐 아니라 급사의 위험이 있다. 본 증례처럼 간세포암이 혈관계를 통해 우심방까지 전이된 경우 노작성 호흡곤란 같은 심부전에 의한 증상을 나타낼 수 있어서 간세포암의 간외 전이를 의심하기는 쉽지 않고, 원발 병소를 찾기 위해서 여러 가지 진단적 검사를 시행하여야 한다. F-18 FDG PET/CT는 기능적으로 암세포의 당대사 항진을 3차원적인 입체 영상으로 국소화하기 때문에 비침습적이며 경제적으로 간세포암의 침범 및 간외전이를 쉽게 확인할 수 있다. 저자들은 호흡곤란을 주소로 내원한 55세 남자 환자에서 PET/CT를 통해서 간세포암과 간세포암의 우심방 침범을 진단하는데 도움을 받았기에 이를 문헌고찰과 함께 보고하는 바이다.

• BMB Reports
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• 제57권2호
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• pp.98-103
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• 2024

The mammalian sirtuin family (SIRT1-SIRT7) has shown diverse biological roles in the regulation and maintenance of genome stability under genotoxic stress. SIRT7, one of the least studied sirtuin, has been demonstrated to be a key factor for DNA damage response (DDR). However, conflicting results have proposed that Sirt7 is an oncogenic factor to promote transformation in cancer cells. To address this inconsistency, we investigated properties of SIRT7 in hepatocellular carcinoma (HCC) regulation under DNA damage and found that loss of hepatic Sirt7 accelerated HCC progression. Specifically, the number, size, and volume of hepatic tumor colonies in diethylnitrosamine (DEN) injected Sirt7-deficient liver were markedly enhanced. Further, levels of HCC progression markers and pro-inflammatory cytokines were significantly elevated in the absence of hepatic Sirt7, unlike those in the control. In chromatin, SIRT7 was stabilized and colocalized to damage site by inhibiting the induction of γH2AX under DNA damage. Together, our findings suggest that SIRT7 is a crucial factor for DNA damage repair and that hepatic loss-of-Sirt7 can promote genomic instability and accelerate HCC development, unlike early studies describing that Sirt7 is an oncogenic factor.

• Korean Journal of Radiology
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• 제20권1호
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• pp.34-49
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• 2019

Conventional transcatheter arterial chemoembolization (c-TACE) is a widely used first-line palliative treatment for patients with unresectable hepatocellular carcinoma (HCC). Despite the effectiveness of c-TACE, to date, technique and procedure scheduling has not yet been standardized. Drug-eluting microspheres (DEMs) were therefore introduced to ensure more sustained and tumor-selective drug delivery for permanent embolization. These DEMs can load various drugs and release them in a sustained manner over a prolonged period. This approach ensures the delivery of high concentrations of chemotherapeutic agents to tumors, without increasing systemic concentrations, and promote tumor ischemia and necrosis. This review summarizes the recent advances in the use of DEM-TACE to treat HCC.

• 핵의학기술
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• 제14권2호
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• pp.155-158
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• 2010

$^{99m}Tc$-macroaggregated albumin (MAA) 를 이용한 간동맥 관류스캔(hepatic arterial perfusion scintigraphy, HAPS)은 간종양의 경동맥 화학요법을 위해 종양의 관류 등을 평가하는데 매우 유용한 방법으로 알려져 있다. 본 연구는 간암환자(hepatocellular carcinoma, HCC)에서의 정상 간 조직에 대한 간세포암의 상대적인 혈류량을 평가하여 종양의 형태, 크기와 lung shunting, tumor to normal ratio (T/N ratio)를 측정하여 HAPS 의 유용성을 알아보고자 하였다. 2009년 6월부터 2009년 9월까지 본원에서 HCC 진단을 받은 환자 7명(평균 64세, 남자 6명, 여자 1명)을 대상으로 하였다. $^{99m}Tc$-MAA 5 mCi를 간 동맥 내에 위치된 카테타를 통하여 주입하고 20분경과 후 HAPS를 시행하였다. 환자의 흉부와 복부가 포함되게 시야를 잡고 anterior, posterior, both lateral 상을 얻고 SPECT를 시행하였다. liver, tumor, lung의 ROI를 그리고 각각의 count와 count/pixel (mean value) 를 구하여 lung shunting, T/N ratio를 구하였다. anterior, posterior 상에서 얻어진 ROI에서 얻어진 tumor size는 2.0~10.8 cm(평균 3.75 cm), liver size 는 8.8~18.5 cm(평균14.6 cm)였다. total tumor와 total normal의 mean value를 통해 얻은 T/N ratio의 범위는 2.41~5.76(평균 3.8)였다. total lung과 total liver의 counts를 통해 얻은 lung shunting의 범위는 3.14~13.92%(평균 6.77%)였다. $^{99m}Tc$-MAA를 이용한 HAPS 는 정상 간 조직에 비해 간세포암내에 강한 방사능 섭취를 보였으며 종양의 크기, 위치 및 T/N ratio를 통한 정량적 관류 평가를 할 수 있었다. 또한 폐 섭취 빈도는 종양 내 동정맥 단락을 추정할 수 있어 간동맥 동위원소 치료 전 단락 유무를 평가할 수 있다는 점이 유용하게 활용될 수 있을 것이다. 따라서 $^{99m}Tc$-MAA를 이용한 HAPS는 간암의 평가 및 치료를 결정 할 수 있는 유용한 검사법으로 이용될 수 있을 것으로 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• 제16권9호
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• pp.3667-3671
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• 2015

Invasion and metastasis is the major cause of tumor recurrence, difficulty for cure and low survival rate. Excavating key transcription factors, which can regulate tumor invasion and metastasis, are crucial to the development of therapeutic strategies for cancers. PU.1 is a master hematopoietic transcription factor and a vital regulator in life. Here, we report that, compared to adjacent non-cancerous tissues, expression of PU.1 mRNA in metastatic hepatocellular carcinoma (HCC), but not primary HCC, was significantly down-regulated. In addition, levels of PU.1 mRNA in metastatic hepatoma cell lines MHCC97L and MHCC97H were much lower than in non-metastatic Hep3B cells. Transwell invasion assays after PU.1 siRNA transfection showed that the invasion of hepatoma cell lines was increased markedly by PU.1 knockdown. Oppositely, overexpression of PU.1 suppressed the invasion of these cells. However, knockdown and overexpression of PU.1 did not influence proliferation. Finally, we tried to explore the potential mechanism of PU.1 suppressing hepatoma cell invasion. ChIP-qPCR analysis showed that PU.1 exhibited a high binding capacity with miR-615-5p promoter sequence. Overexpression of PU.1 caused a dramatic increase of pri-, pre- and mature miR-615-5p, as well as a marked decrease of miR-615-5p target gene IGF2. These data indicate that PU.1 inhibits invasion of human HCC through promoting miR-615-5p and suppressing IGF2. These findings improve our understanding of PU.1 regulatory roles and provided a potential target for metastatic HCC diagnosis and therapy.

• Asian Pacific Journal of Cancer Prevention
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• 제16권17호
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• pp.7441-7447
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• 2015

Objective: This study evaluated the safety and objective response of combining $^{131}I$-labeled-metuximab (Licartin) with transarterial chemoembolization (TACE) in the treatment of unresectable hepatocellular carcinoma (HCC). Materials and Methods: In a multicenter open-label clinical trial, 341 enrolled patients with stage III/IV HCC according to TNM criteria were nonrandomly assigned to a trial group (n=167) and a control group (n=174), undergoing TACE following hepatic intra-arterial injection of licartin or TACE alone from July 2007 to July 2009. Radiopharmaceutical distribution was evaluated. The primary endpoint was overall survival; secondary endpoints included time-to-progression (TTP), toxicity and adverse events (AEs). Results: The radiobiological distribution demonstrated better localization of licartin in liver tumors than other tissues (P<0.01). The organ absorbed doses to liver and red marrow were $3.19{\pm}1.01Gy$ and $0.55{\pm}0.22Gy$, respectively. The 1-year survival rate was significantly higher [79.47% vs. 65.59%, hazard ratio (HR), 0.598, P=0.041] and TTP significantly improved ($6.82{\pm}1.28$ vs. $4.7{\pm}1.14months$, P=0.037) compared with the control group. Patients at stage III achieved more benefit of one year survival than stage IV in the trial group (86.9% vs. 53.8%, P<0.001). There were significant different toxicities in leukocytopenia, thrombocytopenia and increased total bilirubin level [P<0.001, P=0.013, P<0.01, relative risk (RR) 1.63, 1.33, 1.43], but no differences in severe AEs of upper GI hemorrhage and severe liver dysfunction between the groups (5.39% vs. 2.3%, P=0.136). Conclusions: Owing to excellent tumor-targeting, promised efficacy and favourable toxicity profile, the novel combination therapy of licartin and TACE could be applied in patients with unresectable HCC.

• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8069-8073
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• 2014

Background: Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide, with a high mortality. Most patients present with late stage disease, when the treatment options are limited to systemic chemotherapy. The purpose of our study was to evaluate the significance of p53 and EGFR expression in HCC, and to determine whether these two markers correlate with conventional parameters of prognosis. Materials and Methods: Our study included a total of 45 patients, diagnosed histopathologically with HCC. Clinicopathological data including sex, age, tumor necrosis, tumor size, histologic grading, tumor stage, the presence of cirrhosis and chronic hepatitis, were recorded from the Institute database. Three independent microscopic fields were selected for each sample and all the tumor cells within each microscopic field were counted, and then the positive percent of p53 cells were calculated. Three staining patterns were recognized: diffuse, heterogenous and focal. The intensity of EGFR staining was scored on a scale of 0-3+: 0 no staining; 1+ when a weak membrane staining was observed; 2+ when membrane staining is more intense than in 1+, but less than 3+, and 3+ when intense dark brown staining delineated the membrane. To determine the relationship between EGFR expression and p53, we performed double staining in the same HCC specimens. Results: By immunohistochemical staining, p53 protein was detected in tumor cell nuclei in 20 HCCs (44%). We found a significant correlation between the intensity of p53 expression and the histological grade (p=0.008). EGFR expression was detected in 17 (38%) cases, linked to histological grade (p=0.039). Moreover, the intensity of p53 expression was significantly correlated with EGFR intensity (p=0.014). Conclusions: Our results suggest that overexpression of p53 and EGFR plays an important role in hepatocarcinogenesis and contributes to more advanced disease. These markers are not only valuable predictors of prognosis in HCC, but they are also rational targets for new anti-tumor strategies.

• Asian Pacific Journal of Cancer Prevention
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• 제15권14호
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• pp.5951-5957
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• 2014

Background: Traditional Chinese Medicine (TCM) possesses several advantages for treating patients with hepatocellular carcinoma (HCC). The theory of 'Jianpi Huayu Therapy' rooted from 'Jin Kui Yao Lue'is one of the most important therapies in this respect. This study was conducted to investigate the clinical effect and safety of hepatectomy combining with 'Jianpi Huayu Therapy' in the treatment of HCC. Materials and Methods: One hundred and twenty patients with HCC were randomized allocated into hepatectomy combined with 'Jianpi Huayu Therapy' group (treatment group, n=60) and hepatectomy alone group (control group, n=60). Disease- free survival (DFS) and overall survival (OS) were the primary end-points. Liver function at the end of one week after surgery, complications, average days of hospitalization as well as performance status (PS) at the end of one month post operation were also compared. Results: No significant differences existed between two groups on baseline analysis (p>0.05). No treatment related mortality occurred in either group. Post-operative complications were detected among 14 patients (23.3%) in the treatment group, and 12 (20.0%) in the control group (p=0.658). Alanine aminotransferase (ALT) at the end of one week after operation was lower in the treatment than control groups (p=0.042). No significant differences in other indexes of liver function were discovered between two groups. Average days of hospitalization reduced by 0.9 day in treatment group than in control (p=0.034). During follow-up, 104 patients (86.6%) developed recurrence. The rates of 1-, 3-, and 5-year DFS and median DFS for all patients were 77.4%, 26.3%, 9.0% and 25.6 months (range, 6.0~68.0), respectively (78.2%, 29.2%, 14.3% and 28.7 months for the 48 patients in the treatment group and 75.0%, 23.3%, 6.4%, and 22.6 months for the 56 patients in the control group (p=0.045)). 101 patients had died at the time of censor, with 1-, 3-, and 5-year overall survival rates and median survival for all patients of 97.5%, 76.4%, 40.5% and 51.2 months (range, 10.0~72.0), respectively (98.3%, 78.0%, 43.6% and 52.6 months, for treatment and 96.7%, 74.7%, 37.4%, and 49.8 months, for controls, respectively (p=0.048)). Conclusions: Hepatectomy combined with 'Jianpi Huayu therapy'was effective in the treatment of HCC, and reduced post-operative recurrence and metastasis and improved DFS and OS of HCC patients.

• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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• pp.6433-6438
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• 2013

In hepatocellular cancer (HCC), lack of response to chemotherapy and radiation treatment can be caused by a loss of epigenetic modifications of cancer cells. Methionine adenosyltransferase 1A is inactivated in HCC and may be stimulated by an epigenetic change involving promoter hypermethylation. Therefore, drugs releasing epigenetic repression have been proposed to reverse this process. We studied the effect of the demethylating reagent 5-aza-2'-deoxycitidine (5-Aza-CdR) on MAT1A gene expression, DNA methylation and S-adenosylmethionine (SAMe) production in the HCC cell line Huh7. We found that MAT1A mRNA and protein expression were activated in Huh7 cells with the treatment of 5-Aza-CdR; the status of promoter hypermethylation was reversed. At the same time, MAT2A mRNA and protein expression was significantly reduced in Huh7 cells treated with 5-Aza-CdR, while SAMe production was significantly induced. However, 5-Aza-CdR showed no effects on MAT2A methylation. Furthermore, 5-Aza-CdR inhibited the growth of Huh7 cells and induced apoptosis and through down-regulation of Bcl-2, up-regulation of Bax and caspase-3. Our observations suggest that 5-Aza-CdR exerts its anti-tumor effects in Huh7 cells through an epigenetic change involving increased expression of the methionine adenosyltransferase 1A gene and induction of S-adenosylmethionine production.