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Fulltext Genomic analysis of Hepatitis B virus and its association with disease manifestations in Bangladesh

Raihan R, Akbar SMF, Al Mahtab M, Takahashi K, Masumoto J, Tabassum S, et al.

PLoS One, 2019;14(6):e0218744.
PMID: 31251754 DOI: 10.1371/journal.pone.0218744

The direct cytopathic effects of the hepatitis B virus (HBV) on subsequent liver damage are not fully understood in HBV-infected patients. However, associations between the prevalence of various HBV genotypes and the extent of liver damage have been reported from different parts of the world. The purpose of this study was to determine the distribution of HBV genotypes in patients with chronic HBV infection in Bangladesh, a country of 160 million people, of which approximately 3-6 million are chronically infected HBV patients. In addition, whole and partial genome sequencing of HBV was performed to evaluate the relationship between HBV mutations and genotypes. We found that 42% of the patients with low HBV DNA and normal levels of alanine aminotransferase (ALT) had HBV genotype D. In contrast, the HBV genotype C was dominant among patients with high HBV DNA levels (>2000 IU/ml) and elevated ALT and in patients with liver cirrhosis (LC) and hepatocellular carcinomas (HCC). Whole and partial genome sequences of HBV revealed that most patients with LC and HCC had HBV genotype C with mutations at the T1762/A1764 positions. It seems that Bangladesh represents a borderline country, situated within East Asia, which mainly consists of individuals with HBV genotypes B and C, whereas in the western parts of Asia, HBV genotypes A and D are prevalent. Bangladesh is, therefore, an excellent model for the comparison of the pathophysiology of three major HBV genotypes in a single population. The findings of this study suggest a possible association between HBV viral factors and the extent of liver damage in chronic HBV-infected patients.

Matched MeSH terms: Liver Neoplasms
Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma

Swamy SG, Kameshwar VH, Shubha PB, Looi CY, Shanmugam MK, Arfuso F, et al.

Target Oncol, 2017 02;12(1):1-10.
PMID: 27510230 DOI: 10.1007/s11523-016-0452-7

Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer diagnosed worldwide. HCC occurs due to chronic liver disease and is often diagnosed at advanced stages. Chemotherapeutic agents such as doxorubicin are currently used as first-line agents for HCC therapy, but these are non-selective cytotoxic molecules with significant side effects. Sorafenib, a multi-targeted tyrosine kinase inhibitor, is the only approved targeted drug for HCC patients. However, due to adverse side effects and limited efficacy, there is a need for the identification of novel pharmacological drugs beyond sorafenib. Several agents that target and inhibit various signaling pathways involved in HCC are currently being assessed for HCC treatment. In the present review article, we summarize the diverse signal transduction pathways responsible for initiation as well as progression of HCC and also the potential anticancer effects of selected targeted therapies that can be employed for HCC therapy.

Matched MeSH terms: Liver Neoplasms/drug therapy*; Liver Neoplasms/pathology
Selenium supplementation reduced oxidative stress in diethylnitrosamine-induced hepatocellular carcinoma in rats

Mohamed J, Wei WL, Husin NN, Alwahaibi NY, Budin SB

Pak J Biol Sci, 2011 Dec 01;14(23):1055-60.
PMID: 22590839

Selenium in the form of sodium selenite (SSE) is an essential micronutrient which known to possess antioxidant and anticancer properties. This study emphasizes the role of selenium on oxidative stress in experimental rats with N-diethylnitrosamine (DEN) initiated and 2-acetylaminofluorene (2-AAF) promoted multistage hepatocellular carcinogenesis (HCC). Rats were divided randomly into six groups: negative control, positive control (DEN+2-AAF), preventive group (pre-SEE 4 weeks+DEN), preventive control (respective control for preventive group), therapeutic group (DEN+post-SSE 12 weeks) and therapeutic control (respective control for therapeutic group). SSE (4 mg L(-1)) was given to animals before initiation and during promotion phase of HCC. The levels of total protein (TP), conjugated diens (CD), malondialdehyde (MDA), fluorescent pigment (FP), antioxidant activity (AOA) and DNA damage were measured. Supplementation of SSE before the initiation phase of carcinogenicity significantly increased TP and AOA level (p < 0.05) while it decreased the levels of CD, MDA, DNA damage and FP (p < 0.05). Supplementation of SSE during the promotion phase of carcinogenicity significantly decreased the DNA damage and FP level (p < 0.05) and there were negative correlation between the level of AOA and with the level of FP and CD. Thus, supplementation of SSE reduced the adverse changes which occur in liver cancer. However, the chemoprevention effect of SSE was more pronounced when it was supplemented before initiation phase of cancer when compared to promotion phase.

Matched MeSH terms: Liver Neoplasms, Experimental/chemically induced; Liver Neoplasms, Experimental/drug therapy*; Liver Neoplasms, Experimental/metabolism
Synthesis and characterization of gold nanoparticles from Marsdenia tenacissima and its anticancer activity of liver cancer HepG2 cells

Li L, Zhang W, Desikan Seshadri VD, Cao G

Artif Cells Nanomed Biotechnol, 2019 Dec;47(1):3029-3036.
PMID: 31328556 DOI: 10.1080/21691401.2019.1642902

Nowadays, the synthesis and characterization of gold nanoparticles (AuNPs) from plant based extracts and effects of their anticancer have concerned an important interest. Marsdenia tenacissima (MT), a conventional Chinese herbal medicine, has long been used for thousands of years to treat tracheitis, asthma, rheumatism, etc. In this present study, we optimize the reaction of parameters to manage the nanoparticle size, which was categorized by high-resolution transmission electron microscopy (HR-TEM). A different characterization method, for example, UV-visible spectroscopy (UV-vis), fourier-transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) were performed to consider the synthesized AuNPs getting from the MT leaf extract. The MT-AuNPs were analyzed for their cytotoxicity property against HepG2 cells by MTT analysis. The apoptosis was evaluated by using reactive oxygen species (ROS), migration assay, mitochondrial membrane potential (MMP) and apoptotic protein expression. Interestingly, the findings of our study observed the cytotoxicity effect of synthesized MT-AuNPs at a concentration of 59.62 ± 4.37 μg after 24 hrs treatment. Apoptosis was induced by the MT-AuNPs with enhanced ROS, changed MMP and inhibit the migration assay. Finally, the apoptosis was confirmed by the considerable up-regulation of Bax, caspase-9 and caspase-3, while the anti-apoptotic protein expressions of Bcl-2 and Bcl-XL were down-regulated. Although, in this studies, we evaluated the characterization, synthesis and anticancer action of gold nanoparticles from MT (MT-AuNPS) helpful for liver cancer therapeutics.

Matched MeSH terms: Liver Neoplasms/pathology*
Development of a short-term nutritional risk prediction model for hepatocellular carcinoma patients: a retrospective cohort study

Yu J, Lam SK, He L, Wang P, Cao Y

Sci Rep, 2024 Feb 16;14(1):3921.
PMID: 38365922 DOI: 10.1038/s41598-024-54456-4

Malnutrition in patients is associated with reduced tolerance to treatment-related side effects and higher risks of complications, directly impacting patient prognosis. Consequently, a pressing requirement exists for the development of uncomplicated yet efficient screening methods to detect patients at heightened nutritional risk. The aim of this study was to formulate a concise nutritional risk prediction model for prompt assessment by oncology medical personnel, facilitating the effective identification of hepatocellular carcinoma patients at an elevated nutritional risk. Retrospective cohort data were collected from hepatocellular carcinoma patients who met the study's inclusion and exclusion criteria between March 2021 and April 2022. The patients were categorized into two groups: a normal nutrition group and a malnutrition group based on body composition assessments. Subsequently, the collected data were analyzed, and predictive models were constructed, followed by simplification. A total of 220 hepatocellular carcinoma patients were included in this study, and the final model incorporated four predictive factors: age, tumor diameter, TNM stage, and anemia. The area under the ROC curve for the short-term nutritional risk prediction model was 0.990 [95% CI (0.966-0.998)]. Further simplification of the scoring rule resulted in an area under the ROC curve of 0.986 [95% CI (0.961, 0.997)]. The developed model provides a rapid and efficient approach to assess the short-term nutritional risk of hepatocellular carcinoma patients. With easily accessible and swift indicators, the model can identify patients with potential nutritional risk more effectively and timely.

Matched MeSH terms: Liver Neoplasms*
Clinical and chemotherapeutic study of hepatocellular carcinoma in Malaysia: a comparison with African and American patients

Joishy SK, Bennett JM, Balasegaram M, MacIntyre JM, Falkson G, Moertel C, et al.

Cancer, 1982 Sep 15;50(6):1065-9.
PMID: 6286085

Twenty Malaysian patients with unresectable primary liver cell cancer were prospectively studied at the General Hospital, Kuala Lampur, and were compared for clinical features with an equal number each of African and American patients being studied by the Eastern Cooperative Oncology Group. The patients received intravenous 5-FU and oral MeCCNU which was used for the first time in an Asian country. Most of the Malaysian patients were Chinese, belonged to younger age groups, and presented with massive hepatomegaly, jaundice, and fever. Toxicity to MeCCNU invariably occurred in the form of leukopenia or thrombocytopenia, but none life threatening. Partial response was seen in 20% of Malaysians as compared to 16% in Americans and none in Africans. Malaysians achieved a median survival of 16 weeks compared to 28 weeks in Americans and only eight weeks in Africans. Malaysian Chinese patients were all HBc Ab + ve. Other factors which may have played an etiologic role in the induction of primary liver cancer included alcohol, Chinese herbal medicines, aflatoxin and habitual use of medicated rubbing oils.

Matched MeSH terms: Liver Neoplasms/diagnosis; Liver Neoplasms/drug therapy; Liver Neoplasms/epidemiology*
Weight Reduction and Pioglitazone are Cost-Effective for the Treatment of Non-Alcoholic Fatty Liver Disease in Thailand

Chongmelaxme B, Phisalprapa P, Sawangjit R, Dilokthornsakul P, Chaiyakunapruk N

Pharmacoeconomics, 2019 02;37(2):267-278.
PMID: 30430467 DOI: 10.1007/s40273-018-0736-0

INTRODUCTION: This study evaluated lifetime liver-related clinical outcomes, costs of treatment, and the cost-effectiveness of treatment options for non-alcoholic fatty liver disease (NAFLD) in Thailand.
METHODS: A cost-utility analysis using a lifetime Markov model was conducted among Thai patients with NAFLD, from a societal perspective. Pioglitazone, vitamin E, a weight reduction program, and usual care were investigated, with the outcomes of interest being the number of cirrhosis and hepatocellular carcinoma (HCC) cases, life expectancy, quality-adjusted life-years (QALYs), lifetime costs, and the incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were performed.
RESULTS: When compared with usual care, a weight reduction program can prevent cirrhosis and HCC cases by 13.91% (95% credible interval [CrI] 0.97, 20.59) and 2.12% (95% CrI 0.43, 4.56), respectively; pioglitazone can prevent cirrhosis and HCC cases by 9.30% (95% CrI -2.52, 15.24) and 1.42% (95% CrI -0.18, 3.74), respectively; and vitamin E can prevent cirrhosis and HCC cases by 7.32% (95% CrI -4.64, 15.56) and 1.12% (95% CrI -0.81, 3.44), respectively. Estimated incremental life expectancy and incremental QALYs for all treatment options compared with usual care were approximately 0.06 years and 0.07 QALYs, respectively. The lifetime costs of both a weight reduction program and pioglitazone were less than usual care, while vitamin E was $3050 (95% CrI 2354, 3650). The weight reduction program dominated all other treatment options. The probability of being cost-effective in Thailand's willingness-to-pay threshold ($4546/QALY gained) was 76% for the weight reduction program, 22% for pioglitazone, 2% for usual care, and 0% for vitamin E.
CONCLUSIONS: A weight reduction program can prevent cirrhosis and HCC occurrences, and dominates all other treatment options. Pioglitazone and vitamin E demonstrated a trend towards decreasing the number of cirrhosis and HCC cases.

Matched MeSH terms: Liver Neoplasms
Response to Wang et al. Re: How to choose and compare between radiofrequency ablation and transarterial chemoembolization for recurrent hepatocellular carcinoma?

Koh PS, Chan AC

HPB (Oxford), 2017 12;19(12):1133.
PMID: 28943394 DOI: 10.1016/j.hpb.2017.08.007
Matched MeSH terms: Liver Neoplasms*
Fulltext Manilkara zapota (L.) P. Royen Leaf Water Extract Induces Apoptosis in Human Hepatocellular Carcinoma (HepG2) Cells via ERK1/2/Akt1/JNK1 Signaling Pathways

Tan BL, Norhaizan ME, Chan LC

Evid Based Complement Alternat Med, 2018;2018:7826576.
PMID: 30519270 DOI: 10.1155/2018/7826576

Manilkara zapota (L.) P. Royen, called sapodilla, or locally known as ciku, belongs to the family Sapotaceae. We found that Manilkara zapota leaf water extract has cytotoxic effect against human hepatocellular carcinoma (HepG2) cell line in our earlier study. Therefore, this study aimed to explore the anticancer properties of Manilkara zapota leaf water extract in HepG2 cells. We also aimed to unravel yet undiscovered mechanisms and identified several expressed genes whose functions in cytotoxicity activity of Manilkara zapota leaf water extract in HepG2 cells have not been well-studied. The apoptosis and intracellular reactive oxygen species (ROS) activities were analyzed using Annexin V-propidium iodide staining and dichlorodihydrofluorescein diacetate, respectively, by NovoCyte Flow Cytometer. Bax and Bcl-2 expression were assessed using Enzyme-Linked Immunosorbent Assay. The associated molecular pathways were evaluated by quantitative real-time PCR. Overall analyses revealed that Manilkara zapota leaf water extract can increase percentage of early apoptotic cells, induce the formation of ROS, upregulate c-Jun N-terminal kinase 1 (JNK1) and inducible nitric oxide synthase (iNOS), and reduce Akt1 and vascular endothelial growth factor A (VEGFA) transcriptional activities. Our data suggest that Manilkara zapota leaf water extract can suppress the growth of HepG2 cells via modulation of ERK1/2/Akt1/JNK1 transcriptional expression.

Matched MeSH terms: Liver Neoplasms
Fulltext VIPoma syndrome: challenges in management

Adam N, Lim SS, Ananda V, Chan SP

Singapore Med J, 2010 Jul;51(7):e129-32.
PMID: 20730389

Vasoactive intestinal peptide-producing tumour (VIPoma) or Verner-Morrison syndrome is a very rare neuroendocrine tumour. It occurs in less than ten percent of all pancreatic islet cell tumours, and about 70 percent to 80 percent of these tumours originate from the pancreas. Diagnosis is characteristically delayed. The first-line treatment is surgical. It may be curative in forty percent of patients with benign and non-metastatic disease. Palliative surgery is indicated in extensive disease, followed by conventional somatostatin analogue (octreotide) therapy. Somatostatin analogues improve hormone-mediated symptoms, reduce tumour bulk and prevent local and systemic effects. We present a female patient with VIPoma syndrome, which had metastasised to the liver at diagnosis. The patient underwent palliative Whipple procedure and subsequent cytoreductive radiofrequency ablations to her liver metastases. Unfortunately, after symptomatic improvement for three years, her disease progressed. Currently, she is on daily octreotide, achieving partial control of her symptoms.

Matched MeSH terms: Liver Neoplasms/secondary*; Liver Neoplasms/surgery
Barcelona Clinic Liver Cancer and Hong Kong Liver Cancer staging systems for prediction of survival among Hepatocellular Carcinoma patients

Karuthan SR, Koh PS, Chinna K, Chan WK

Med J Malaysia, 2021 03;76(2):199-204.
PMID: 33742628

INTRODUCTION: We aimed to compare the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC) staging systems.
MATERIALS AND METHODS: This is a retrospective study on patients with newly diagnosed hepatocellular carcinoma (HCC) at the University Malaya Medical Centre between 2011 and 2014. Survival times were analysed using the Kaplan- Meier procedure and comparison between groups was done using the log rank test.
RESULTS: The data of 190 patients was analysed. Chronic hepatitis B was the most common aetiology for HCC (43.7%), but a large proportion was cryptogenic or non-alcoholic steatohepatitis-related (41.6%). Only 11.1% were diagnosed early (BCLC Stage 0-A) while majority were diagnosed at an intermediate stage (BCLC Stage B, 53.7%). The median survival rate was significantly different between the different groups when either of the staging systems was used (p<0.05 for all comparisons). However, the two staging systems lacked agreement (weighted kappa 0.519, 95%CI: 0.449, 0.589) with significant difference in median survival rates between BCLC Stage A and HKLC Stage 2, and between BCLC Stage C and HKLC Stage 4.
CONCLUSION: Both staging systems were able to stratify patients according to survival, but they only had moderate agreement with significant differences observed in two groups of the staging systems.

Matched MeSH terms: Liver Neoplasms
Epidemiology of non-alcoholic fatty liver disease in Asia

Wong SW, Chan WK

Indian J Gastroenterol, 2020 02;39(1):1-8.
PMID: 32152903 DOI: 10.1007/s12664-020-01018-x

The growing burden of non-alcoholic fatty liver disease (NAFLD) parallels the increasing prevalence of obesity in Asia. The overall prevalence of NAFLD in Asia is now estimated to be 29.6% and may have surpassed that in Western populations. NAFLD increases with increasing age and is closely associated with metabolic syndrome. Ethnic differences exist in the prevalence of NAFLD, but the underlying factors are unclear. There were initial concerns about lean NAFLD being associated with more severe liver disease and increased mortality, but subsequent studies suggested otherwise. Only some NAFLD patients progress to develop advanced liver fibrosis and cirrhosis, while the liver status remains unchanged in the majority; fibrosis stage is the most important predictor of disease-specific mortality in NAFLD. Surveillance for hepatocellular carcinoma (HCC) remains a challenge due to undiagnosed cirrhosis and the development of HCC in non-cirrhotic NAFLD patients. Diabetes mellitus shares a bidirectional relationship with NAFLD; NAFLD is highly prevalent among patients with diabetes mellitus, and diabetes mellitus is associated with more severe NAFLD. Chronic hepatitis B (CHB) is a major cause of chronic liver disease in Asia; NAFLD and CHB are increasingly observed together because of the increasing prevalence of NAFLD. Despite studies reporting favorable virologic outcome in CHB patients with NAFLD, NAFLD has been found to be independently associated with fibrosis progression and poorer prognosis in CHB patients. Therefore, NAFLD in CHB patients should be given more attention.

Matched MeSH terms: Liver Neoplasms/etiology; Liver Neoplasms/epidemiology
Epidemiology of non-alcoholic fatty liver disease-related hepatocellular carcinoma and its implications

Wong SW, Ting YW, Chan WK

JGH Open, 2018 Oct;2(5):235-241.
PMID: 30483595 DOI: 10.1002/jgh3.12070

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related mortality worldwide. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver pathology that is characterized by the excessive accumulation of fat in the liver attributable to overnutrition and is strongly associated with the metabolic syndrome. Non-alcoholic steatohepatitis is the more severe form of NAFLD that is defined histologically by the presence of lobular inflammation and hepatocyte ballooning. Non-alcoholic steatohepatitis patients have a greater tendency to develop advanced liver fibrosis, cirrhosis, and HCC. This review focuses on the epidemiology of NAFLD-related HCC and its implications. NAFLD has been estimated to contribute to 10-12% of HCC cases in Western populations and 1-6% of HCC cases in Asian populations. NAFLD-related HCC is expected to increase in Asian populations, in line with the increased prevalence of NALFD similar to that of Western populations in recent years. The increasing burden of NAFLD-related HCC over time has been demonstrated in studies from both Western and Asian populations. Certain factors such as ethnicity, obesity, and diabetes mellitus appear to have an incremental effect on the risk of developing HCC among NAFLD patients. The difficulty in identifying NAFLD patients with cirrhosis and the possibility of HCC developing in noncirrhotic NAFLD patients are challenges that need to be addressed. Further understanding of these gaps may contribute to better surveillance strategies for the early detection of HCC in NAFLD patients to reduce the mortality and improve the survival of these patients.

Matched MeSH terms: Liver Neoplasms
Metastatic hepatocellular carcinoma presenting as a sphenoid sinus mass and meningeal carcinomatosis

Hashim H, Rahmat K, Abdul Aziz YF, Chandran PA

Ear Nose Throat J, 2014 Jun;93(6):E20-3.
PMID: 24932824

We report the case of a 30-year-old woman who was referred to us for evaluation of a 2-week history of fever, headache, vomiting, bilateral ptosis, and blurred vision. Imaging obtained by the referring institution had identified a sphenoid sinus mass and diffuse meningeal infiltration, which was thought to represent an infective process. We subsequently identified the mass as a metastatic hepatocellular carcinoma (HCC). The patient was placed under palliative care, and she died 1 month later. Metastases to the sphenoid sinus from any primary source are very rare, and they are generally not considered in the radiologic differential diagnosis. HCC is known to metastasize to the lung, lymph nodes, and musculoskeletal system; again, reported cases of metastasis to the sphenoid sinus are rare. Indeed, our review of the English-language literature found only 6 previously reported cases of sinonasal metastasis of a primary HCC. A diagnosis of a sinonasal metastasis is more difficult in a patient who has no previous diagnosis of a primary malignancy. In presenting this case, our aim is to remind readers of this possibility.

Matched MeSH terms: Liver Neoplasms/pathology*; Liver Neoplasms/radiography
Fulltext Doubly Spliced RNA of Hepatitis B Virus Suppresses Viral Transcription via TATA-Binding Protein and Induces Stress Granule Assembly

Tsai KN, Chong CL, Chou YC, Huang CC, Wang YL, Wang SW, et al.

J Virol, 2015 Nov;89(22):11406-19.
PMID: 26339052 DOI: 10.1128/JVI.00949-15

The risk of liver cancer in patients infected with the hepatitis B virus (HBV) and their clinical response to interferon alpha therapy vary based on the HBV genotype. The mechanisms underlying these differences in HBV pathogenesis remain unclear. In HepG2 cells transfected with a mutant HBV(G2335A) expression plasmid that does not transcribe the 2.2-kb doubly spliced RNA (2.2DS-RNA) expressed by wild-type HBV genotype A, the level of HBV pregenomic RNA (pgRNA) was higher than that in cells transfected with an HBV genotype A expression plasmid. By using cotransfection with HBV genotype D and 2.2DS-RNA expression plasmids, we found that a reduction of pgRNA was observed in the cells even in the presence of small amounts of the 2.2DS-RNA plasmid. Moreover, ectopic expression of 2.2DS-RNA in the HBV-producing cell line 1.3ES2 reduced the expression of pgRNA. Further analysis showed that exogenously transcribed 2.2DS-RNA inhibited a reconstituted transcription in vitro. In Huh7 cells ectopically expressing 2.2DS-RNA, RNA immunoprecipitation revealed that 2.2DS-RNA interacted with the TATA-binding protein (TBP) and that nucleotides 432 to 832 of 2.2DS-RNA were required for efficient TBP binding. Immunofluorescence experiments showed that 2.2DS-RNA colocalized with cytoplasmic TBP and the stress granule components, G3BP and poly(A)-binding protein 1 (PABP1), in Huh7 cells. In conclusion, our study reveals that 2.2DS-RNA acts as a repressor of HBV transcription through an interaction with TBP that induces stress granule formation. The expression of 2.2DS-RNA may be one of the viral factors involved in viral replication, which may underlie differences in clinical outcomes of liver disease and responses to interferon alpha therapy between patients infected with different HBV genotypes.

Matched MeSH terms: Liver Neoplasms/epidemiology; Liver Neoplasms/virology
Tissue microarray immunohistochemical profiles of p53 and pRB in hepatocellular carcinoma and hepatoblastoma

Azlin AH, Looi LM, Cheah PL

Asian Pac J Cancer Prev, 2014;15(9):3959-63.
PMID: 24935581

The tumour suppressor genes, p53 and pRb, are known to play important roles in neoplastic transformation. While molecular routes to the uncontrolled growth of hepatocytes, leading to primary liver cancer have generated considerable interest, the roles of p53 and pRb mutations in hepatocellular carcinoma (HCC) and hepatoblastoma (HB) remain to be clarified. We examined the immunohistochemical expression of p53 and pRb gene products in 26 HCC and 9 HB, sampled into tissue microarray blocks. 10 (38%) of 26 HCC showed > 10% tumour nuclear staining for p53 protein, 3 of these also being HbsAg positive. Conversely, none of 9 HB expressed nuclear p53 immunopositivity. Some 24 (92%) HCC and 8 (89%) HB showed loss of pRb nuclear expression. Two of the 26 HCC and one of the 9 HB showed >10% tumour nuclear staining for pRb protein. Our results suggest that p53 does not have an important role in the development of HB but may contribute in HCC. There is also loss of pRb expression in the majority of HCC and HB, supporting loss of pRb gene function in the hepatocarcinogenesis pathway. However, a comparison of the staining profiles of p53 and pRb proteins in HCC and HB did not reveal a consistent pattern to differentiate between the two types of tumours immunohistochemically. Hence the use of p53 and pRB protein expression has no contribution in the situation where there is a diagnostic difficulty in deciding between HCC and HB.

Matched MeSH terms: Liver Neoplasms/genetics*; Liver Neoplasms/pathology
Rapidly increasing liver progenitor cell numbers in human regenerating liver after portal vein ligation and liver partition

Lin KH, Hsu HT, Teng TH, Lin PY, Ko CJ, Hsieh CE, et al.

Malays J Pathol, 2017 Dec;39(3):289-291.
PMID: 29279592

BACKGROUND: Liver regeneration is dependent on the proliferation of hepatocytes. Hepatic progenitor cells are intra-hepatic precursor cells capable of differentiating into hepatocytes or biliary cells. Although liver progenitor cell proliferation during the regenerative process has been observed in animal models of severe liver injury, it has never been observed in vivo in humans because it is unethical to take multiple biopsy specimens for the purpose of studying the proliferation of liver progenitor cells and the roles they play in liver regeneration. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a staged procedure for inducing remnant liver hypertrophy so that major hepatectomy can be performed safely. This staged procedure allows for liver biopsy specimens to be taken before and after the liver begins to regenerate.
CASE PRESENTATION: The liver progenitor cell proliferation is observed in a patient undergoing ALPPS for a metastatic hepatic tumour. Liver biopsy is acquired before and after ALPPS for the calculation of average number of liver progenitor cell under high magnification examination by stain of immunomarkers. This is the first in vivo evidence of growing liver progenitor cells demonstrated in a regenerating human liver.

Matched MeSH terms: Liver Neoplasms/surgery
1H NMR-Based Metabolic Profiles Delineate the Anticancer Effect of Vitamin C and Oxaliplatin on Hepatocellular Carcinoma Cells

Lin C, Dong J, Wei Z, Cheng KK, Li J, You S, et al.

J Proteome Res, 2020 02 07;19(2):781-793.
PMID: 31916767 DOI: 10.1021/acs.jproteome.9b00635

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Because of its high recurrence rate and heterogeneity, effective treatment for advanced stage of HCC is currently lacking. There are accumulating evidences showing the therapeutic potential of pharmacologic vitamin C (VC) on HCC. However, the metabolic basis underlying the anticancer property of VC remains to be elucidated. In this study, we used a high-resolution proton nuclear magnetic resonance-based metabolomics technique to assess the global metabolic changes in HCC cells following VC treatment. In addition, the HCC cells were also treated with oxaliplatin (OXA) to explore the potential synergistic effect induced by the combined VC and OXA treatment. The current metabolomics data suggested different mechanisms of OXA and VC in modulating cell growth and metabolism. In general, VC treatment led to inhibition of energy metabolism via NAD+ depletion and amino acid deprivation. On the other hand, OXA caused significant perturbation in phospholipid biosynthesis and phosphatidylcholine biosynthesis pathways. The current results highlighted glutathione metabolism, and pathways related to succinate and choline may play central roles in conferring the combined effect between OXA and VC. Taken together, this study provided metabolic evidence of VC and OXA in treating HCC and may contribute toward the potential application of combined VC and OXA as complementary HCC therapies.

Matched MeSH terms: Liver Neoplasms
Rapid metastasis of breast cancer cells from primary tumour to liver

Kumar SS, Radhakrishnan AK, Cheong SK

Pak J Biol Sci, 2010 Apr 01;13(7):303-15.
PMID: 20836285

The aim of this study was to establish an animal model of mammary carcinoma metastasis to discern the in vivo effects of growth and spread of breast cancer. Six-week-old female BALB/c mice were inoculated with 4T1 murine breast cancer cells. Mice weight and primary tumour mass volume were regularly recorded to study the physical effects of a vigorously growing and spreading of cancer cell line. Gross and histological studies were carried out to determine the approximate day of metastatic onset. Production of IFN-gamma was assessed by ELISA to understand its role in tumour growth and metastasis. Lymphocyte markers such as CD8+, CD25 and CD49b were analysed to elucidate its role in tumour growth and progression. Present study showed that the metastatic onset occurs approximately 11 days after the mice were inoculated with the 4T1 murine breast cancer cells. Gross studies showed hepatosplenomegaly. The breast cancer cells from primary tumour were found to spread rapidly to the liver on day 11. IFN-gamma production was higher in inoculated mice serum compared to control mice serum. Higher numbers of CD8+, CD25 and CD49b cells were observed in the peripheral blood of inoculated mice, compared to control mice. In conclusion, the 4T1 murine breast cancer cells can migrate and metastasise rapidly to the liver, eliciting various immune responses.

Matched MeSH terms: Liver Neoplasms/pathology; Liver Neoplasms/secondary*
Tumour necrosis factor alpha down-regulates the expression of peroxisome proliferator activated receptor alpha (PPARα) in human hepatocarcinoma HepG2 cells by activation of NF-κB pathway

Lim WS, Ng DL, Kor SB, Wong HK, Tengku-Muhammad TS, Choo QC, et al.

Cytokine, 2013 Jan;61(1):266-74.
PMID: 23141142 DOI: 10.1016/j.cyto.2012.10.007

Peroxisome proliferator activated receptor-alpha (PPARα) plays a major role in the regulation of lipid and glucose homeostasis, and inflammatory responses. The objectives of the study were to systematically investigate the effects of TNF-α and its regulatory pathway on PPARα expression in HepG2 cells using Real-Time RT-PCR and western blot analysis. Here, TNF-α suppressed PPARα mRNA expression in a dose- and time-dependent manner at the level of gene transcription. Pre-treatment of cells with 10μM of Wedelolactone for 2h was sufficient to restore PPARα expression to basal levels and also affected the expression of PPARα-regulated genes. This study also demonstrated that TNF-α represses PPARα expression by augmenting the activity of canonical NF-κB signalling pathway. This was shown by the abrogation of TNF-α-mediated PPARα down-regulation, after both p65 and p50 were knocked down via siRNA. The IKK contributes to IκBα degradation and mediates inducible phosphorylation of p105 at Ser933. Surprisingly, phosphorylation of p65 at Ser468 and Ser536 were severely abrogated with Wedelolactone inhibition, suggesting that Ser468 and Ser536, but not Ser276, may mediate the TNF-α inhibitory action on PPARα gene expression. These results suggest that TNF-α might, at least in part, suppress PPARα expression through activation of IKK/p50/p105/p65 pathway. Furthermore, phosphorylation of p65 at Ser468 and Ser536 may play a crucial role in the mechanism that limits PPARα production in the human HepG2 cells.

Matched MeSH terms: Liver Neoplasms/metabolism

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