NF-κB and STAT3 - key players in liver inflammation and cancer.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

Rho GTPase and Wnt Signaling Pathways in Hepatocarcinogenesis

Notch signaling and new therapeutic options in liver disease

The Mutational and Transcriptional Landscapes of Hepatocarcinogenesis in a Rat Model.

Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States.

An unusual risk factor for intrahepatic cholangiocarcinoma

<p>Primary liver cancer is one of the most commonly occur-ring malignancies, albeit one with a deadly consequence as it ranks second in males and sixth in females as a cause of cancer-related death [1, 2]. In this regard, hepatocellular carcinoma (HCC) constitutes almost 90% of confirmed primary liver cancer cases [3]. Despite the advances in clinical classifications of HCC according to patient-related and disease-related criteria (e.g., the Barcelona Clinic liver cancer system) [4], exploring the biological diversity of HCC have lagged behind. The biological diversity of HCC is ex-pected to come from a diverse set of etiological factors (Hepatitis-B virus, Hepatitis-C virus, non-alcoholic stea-tohepatitis, and aflatoxin, among other things), all of which are expected to drive the pathogenesis of HCC via various pathways. In the current issue of AMOR, Youssef and co-workers explored the potential involvement of the cofactor of BRCA1 (COBRA1) in HCC pathogenesis [5]. COBRA1 has been incriminated in the pathogenesis of a number of other solid tumors, notably breast cancer. In the current study, the authors investigated the expression of COBRA1 in several HCC cell lines, ranging from low- to high-grade HCC cell lines. Their results showed that the COBRA1 protein was highly expressed in the low-grade HCC cell line, while significantly down-regulated in high-grade HCC cell lines. This preliminary study indicates that COBRA1 may indeed play a role in HCC pathogenesis and progression, and should be further investigated moving forward.</p><p>Primary liver cancer is one of the most commonly occurring malignancies, albeit one with a deadly consequence as it ranks second in males and sixth in females as a cause of cancer-related death [1,2]. In this regard, hepatocellular carcinoma (HCC) constitutes almost 90% of confirmed primary liver cancer cases [3].</p><p>Despite the advances in clinical classifications of HCC according to patient-related and disease-related criteria (<em>e.g.</em>, the Barcelona Clinic liver cancer system) [4], exploring the biological diversity of HCC have lagged behind. The biological diversity of HCC is expected to come from a diverse set of etiological factors (Hepatitis-B virus, Hepatitis-C virus, non-alcoholic steatohepatitis, and aflatoxin, among other things), all of which are expected to drive the pathogenesis of HCC via various pathways.</p><p>In the current issue of AMOR, Youssef and co-workers explored the potential involvement of the cofactor of BRCA1 (COBRA1) in HCC pathogenesis [5]. COBRA1 has been incriminated in the pathogenesis of a number of other solid tumors, notably breast cancer. In the current study, the authors investigated the expression of COBRA1 in several HCC cell lines, ranging from low- to high-grade HCC cell lines. Their results showed that the COBRA1 protein was highly expressed in the low-grade HCC cell line, while significantly down-regu- lated in high-grade HCC cell lines. This preliminary study indicates that COBRA1 may indeed play a role in HCC pathogenesis and progression, and should be further investigated moving forward.</p>

Liver cancer is one of the most common human malignancies. Ranks as the third leading cause of cancer-related mortality and fifth commonest human malignancy worldwide, hepatocellular carcinoma (HCC) is the major form (more than 80%) of primary liver cancer. The pathogenesis of HCC is a complicated long-term process that involves the activation of oncogenes and inactivation of tumor suppressor genes caused by genetic and epigenetic alterations. Thus, a better understanding of the genetic and epigenetic alterations during the development and progression of HCC is of great importance for early diagnosis and treatment.
\nEpidemiological studies found that chronic HBV and/or HCV infection, alcohol consumption and aflatoxin B intake are the most common risk factors for HCC incidence. Chronic inflammation is an important factor in the incidence and progression of many human malignancies, up to 20% of human cancers are developed from chronic inflammation, and HCC is the case.
\nComparison of transcriptomic and proteomic profiles is a powerful strategy to study oncogenic targets during disease progression in cancer research. Previously, a RNA sequencing (RNA-Seq) of 3 paired HCC tumor and non-tumor tissues was carried out in the Laboratory of Cancer Genetics at The University of Hong Kong to identify genetic alterations of HCC. According to the RNA sequencing result, up-regulation of PIM2was observed in HCC tumor tissues compared with paired non-tumor tissues.
\nPIM2 belongs to PIM serine/threonine kinase family, which consists of three members, PIM1, PIM2 and PIM3. Up-regulation of PIM2 was found in many human malignancies, such as leukemia, lymphoma, prostate cancer and ovarian cancer. This study aims to characterize the roles of PIM2 in the pathogenesis and progression of HCC. In this study, up-regulation of PIM2was frequently observed in HCC patients, and following clinical pathological study showed that HCC patients with higher PIM2 expression level had a higher recurrence rate (P = 0.031) and poorer prognosis (P = 0.001). Functional studies showed that PIM2 overexpression could promote HCC cell proliferation, resistance to chemotherapy, tumorigenesis and metastasis in nude mice; and PIM2 knockdown by shRNA could effectively inhibit these phenotypes. Mechanistic studies revealed that PIM2 overexpression could activate NF-κB signaling pathway through or partly through up-regulating phosphorylation level of RIPK2, a well-known potent activator of NF-κB signaling.
\nFurthermore, I found TNFα, a pro-inflammatory cytokine, could stimulate the expression of PIM2in HCC cells and PIM2 overexpression in HCC cells could in turn up-regulate the expression level of TNFα. In addition, the mRNA levels of PIM2 and TNFα in HCC patients are closely correlated (Pearson r = 0.5332, P < 0.0001). I also found that PIM kinase inhibitor AZD1208 treatment could effectively attenuate HCC cells’ tumorigenic ability both in vitro and in vivo. Collectively, my study revealed a positive feedback loop between an inflammatory factor and a proto-oncogene that contributed to the tumorigenesis and progression of HCC, and PIM kinases may serve as a therapeutic target in the treatment of HCC.

Hepatitis C virus (HCV) infection is a global health problem affecting 170 million individuals worldwide. In the United States, there are approximately 7 million adults and 100,000 children chronically infected with HCV (1,2). The importance of HCV infection stems from its proclivity to cause insidious liver damage over many years, including chronic hepatitis, cirrhosis, and liver cancer. In adults, HCV infection is a leading cause for liver cancer worldwide (3). The financial burden of this viral infection is staggering, with projected medical costs of $10.7 billion in adults from 2010 to 2019 and approximately $426 million during the next 10 years in children (4,5). The epidemiology, clinical outcome, and risk factors associated with progression of HCV-related liver disease are fairly well characterized in adults. Although the natural history of childhood HCV infection is poorly defined, it appears to be an indolent disease in most children (6–13); however, progressive liver disease, including chronic hepatitis and cirrhosis necessitating liver transplantation, can occur in children (14,15). Unlike in adults, liver cancer, particularly hepatocellular carcinoma (HCC), is rare in children (16), but it was described in 2 young adults infected with HCV during childhood (17). Herein we extend these observations and present 2 children with chronic hepatitis C who developed HCC as adolescents. To our knowledge, they are the youngest HCV-infected patients to be reported as having this complication. These cases illustrate the potentially ominous course of HCV infection, and highlight the importance of remaining vigilant for complications via periodic evaluation in young patients with this infection. We performed a retrospective chart review of 2 adolescents with HCV infection who developed HCC. This work was exempt from approval by the institutional review boards of all of the participating centers. PATIENT 1 The child was a 13-year-old white girl who had received a T cell–depleted allogeneic stem cell transplant for recurrent acute myelogenous leukemia 7 years earlier, in May 1986. The stem cell transplant preconditioning regimen included Cytoxan and fractionated total body irradiation. Her posttransplant course was complicated by Escherichia coli urinary tract infection, hemorrhagic cystitis, and graft-versus-host disease involving her skin. Two months after stem cell transplant, she was hospitalized for Varicella zoster infection of the trigeminal nerve and results of liver tests were abnormal: total bilirubin 7.5 mg/dL (direct reacting fraction 2.5 mg/dL), aspartate aminotransferase (AST) 1206 IU/L (normal < 40 IU/L), and alanine aminotransferase (ALT) 1880 IU/L (normal < 40 IU/L). Her serological evaluation excluded infection with Epstein-Barr virus, hepatitis B virus, cytomegalovirus, and Toxoplasma gondii. Abdominal sonogram yielded normal results. Values of AST and ALT remained intermittently abnormal and were ascribed to possible chronic graft-versus-host disease. She subsequently developed aseptic necrosis of the right ankle, as well as growth hormone deficiency, hypothyroidism, attention deficit disorder, and hypertension, for which she was prescribed a short course of growth hormone (discontinued because of liver dysfunction), L-thyroxine, methylphenidate, and propranolol, respectively. In May 1993, 7 years after her stem cell transplant, she experienced an episode of hematemesis and melena for which she received packed red blood cells and was prescribed cimetidine by her general physician. Melena recurred 3 days before a scheduled routine visit with pediatric oncologists at the University of Florida; she then had an episode of hematemesis in the oncology clinic and she was hospitalized for further management. The family history was significant for cancer of the stomach, pancreas, and lung, as well as peptic ulcer disease. On initial examination, the patient was a teenager in no acute distress. The heart and respiratory rates were 160 beats and 32 breaths per minute, respectively, and blood pressure was 127/55 mmHg. The remainder of the physical examination was normal except for a systolic heart murmur and the presence of black, tarry stools that were guaiac positive. In particular, neither liver nor spleen was enlarged and there were no other stigmata of chronic liver disease. Initial laboratory evaluation revealed a hemoglobin concentration of 4.5 g/dL, white blood cell count 17.5 × 106/L, and platelets 210 × 106/L; results of routine serum electrolytes, blood urea nitrogen, creatinine, glucose, calcium, phosphorus, alkaline phosphatase, total bilirubin, and direct bilirubin were normal; the AST and ALT were elevated at 89 IU/L and 55 IU/L (normal < 40 IU/L), respectively. Hepatitis A and B virus serology were negative; α1-antitrypsin and ceruloplasmin levels were normal as were the results of prothrombin and partial thromboplastin time. Her serum tested positive for HCV by enzyme immunoassay (optical density > 5.5); nucleic amplification tests were not commercially available at the time, but she had detectable HCV RNA by an in-house polymerase chain reaction assay (18). An abdominal sonogram again yielded normal findings except for ascites, and esophagogastroduodenoscopy revealed Candida esophagitis and varices in the distal esophagus and gastric fundus without active bleeding. Histological review of liver tissue obtained by percutaneous needle biopsy showed focal chronic portal and lobular inflammation with mild portal fibrosis and macrovesicular steatosis. The patient was treated with packed red blood cells, fluconazole, and famotidine, and was subsequently discharged home. During the next 4 months, and despite the addition of propranolol to the medical regimen, she had several episodes of hematemesis. Sclerotherapy of the esophageal varices led to no further bleeding but variceal size remained unchanged. While the patient was being evaluated for liver transplantation at 13 years of age, in February 1994 the α-fetoprotein (AFP) concentration was noted to be elevated (2740 ng/mL; normal < 8.9 ng/mL); computerized axial tomography (CT) scan of the abdomen revealed 2 low-attenuation lesions in the right lobe of the liver, measuring approximately 4 and 6 cm in largest diameter, respectively. There were no abnormalities noted on the CT scan of her chest and bone scan and she underwent a right hepatectomy. Histological review of the excised liver revealed chronic active hepatitis, cirrhosis, and multinodular HCC with the margins of the sample free of tumor. The AFP levels initially decreased but then increased by the end of June 1994 (Fig. 1A) and several low-attenuation lesions were noted in the left lobe of the liver via abdominal CT scan. The cholestasis worsened and repeat CT scan of the abdomen in September 1994 showed bile duct dilatation; the AFP was 6470 ng/mL. The patient underwent palliative biliary stent placement and died at home shortly thereafter.FIG. 1: Biochemical profiles of (A) patient 1 and (B) patient 2. AFP = α-fetoprotein.PATIENT 2 The child was a 14-year-old African American girl who presented with anasarca and liver dysfunction in September 2001. She was the product of a cesarean section from a mother infected with HCV and human immunodeficiency virus (HIV). This patient presented to an outside hospital 4 months earlier with pedal edema and mild respiratory distress. Laboratory studies at that time revealed liver dysfunction with an AST and ALT of 158 IU/L and 146 IU/L, respectively (normal < 40 IU/L for both); the serum albumin concentration was 2.5 g/dL, and the prothrombin time was 14.4 seconds (normal <12 seconds). The hemoglobin concentration was 11.6 g/dL, white blood cell count 4.2 × 106/L, and platelet count 81 × 106/L. She had detectable HCV RNA in serum at 83200 IU/mL (Amplicor V2.0, Roche Diagnostics, Indianapolis, IN) and the HCV genotype was 1a. The AFP concentration was mildly elevated at 39.8 ng/mL (normal <8.9 ng/mL; Fig. 1B). Hepatitis A and B virus and HIV serology were negative and other potential causes of liver dysfunction including α1-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease were excluded with appropriate serological tests. She was prescribed spironolactone, furosemide, ursodeoxycholic acid, and vitamin K and referred to our liver center for consideration of antiviral treatment and liver transplantation. At the time of presentation, findings on a physical examination were normal except for the presence of ascites and a firm liver edge that was palpable 8 cm below the right costal margin at the midclavicular line. Results of liver tests were persistently abnormal: AST, ALT, and total bilirubin concentrations were 156 IU/L, 112 IU/L, and 4.9 mg/dL, respectively; the serum albumin level was 2.8 mg/dL, the prothrombin time was 18.1 seconds, and the plasma ammonia concentration was 95 mg/dL. Histological examination of liver tissue obtained by a transjugular approach showed minimal portal lymphocytic infiltration, intrahepatic cholestasis, and rare foci of piecemeal necrosis, but no significant lobular inflammation, fibrosis, or steatosis. She was prescribed a salt-restricted diet, neomycin, lactulose, and monthly parenteral vitamin K. There was concern that antiviral therapy would precipitate further worsening of her advanced liver disease and she was listed for liver transplantation. During the next few months she experienced recurrent epistaxis and pedal edema. The concentration of AFP increased to 76.6 ng/mL within 5 months (Fig. 1B), and results of a sonogram and CT of her abdomen yielded normal results except for ascites and a nodular-appearing liver. The patient remained clinically stable during the ensuing 5 months but then developed pancreatitis, E coli bacteremia, and Klebsiella urosepsis, resulting in septic shock necessitating mechanical ventilation, vasopressors, and admission to an outside pediatric intensive care unit. She was transferred to our hospital with grade III encephalopathy. Her clinical course was complicated by renal dysfunction consistent with hepatorenal syndrome requiring hemodialysis. A suitable cadaveric liver allograft became available and she underwent emergent split liver transplant. At the time of surgery, 5 L of ascitic fluid were noted in her abdominal cavity, as was severe portal hypertension. Unfortunately, the transplant procedure was complicated by extensive retroperitoneal bleeding and cardiopulmonary arrest. She was successfully resuscitated, the surgical wound was packed open, and she was returned to pediatric intensive care. She required reoperation a few hours later because massive bleeding persisted and she continued to be unresponsive to large amounts of blood products. The transplanted liver appeared nonfunctional and was removed. Although a portosystemic shunt was constructed, the massive retroperitoneal bleeding continued, and the patient experienced another cardiac arrest and expired despite resuscitation attempts. Histologically, the native explanted liver was cirrhotic and contained multiple foci of lobular necrosis and dysplastic nodules. A single 1.5-cm nodule of well-differentiated HCC also was discovered. DISCUSSION Although chronic hepatitis C is regarded as a major cause of liver morbidity in adults, this viral infection is generally believed to be indolent in children. However, chronic HCV infection leads to significant liver dysfunction in a proportion of children, severe enough to necessitate liver replacement in some (14,15). In addition, hepatocellular carcinoma developed in 2 young adults with transfusion-acquired HCV infection many years after undergoing successful cancer treatment (17). This report of HCC during adolescence further substantiates the notion that HCV infection can lead to devastating consequences even in the second decade of life. Hepatocellular carcinoma is a common cancer in adults and HCV infection accounts for a significant proportion of the cases (3). Hepatitis C virus–related liver cancer usually but not exclusively arises in the context of cirrhosis. Although the pathogenesis of hepatocellular carcinoma is poorly understood, repeated cycles of liver injury with attendant regeneration and repair likely play a pivotal role in its development. Important factors that appear to increase the risk for HCV-related liver cancer in adults include male sex, older age at diagnosis and at acquisition of virus, severity of liver disease at presentation, co-infection with hepatitis B virus or HIV, and excessive alcohol consumption, as well as possibly liver steatosis and diabetes mellitus (3). The occurrence of HCC in children is rare in comparison with adult occurrence, and a predisposing oncogenic cause is identified in only a small minority of cases (16). The detection of serological markers of HCV in adults with hepatocellular carcinoma is generally sufficient to establish a causal relation between this infection and cancer. Therefore, the recognition of HCV antibodies and HCV RNA in serum, in the absence of other predisposing factors, strongly supports this viral infection as the cause of liver cancer in our patients. Secondary malignancies are relatively common among cancer survivors (19), especially in those who receive growth hormone therapy (20) such as our first patient. Interestingly, liver cancer is not reported in large cohorts of patients surviving cancer, even in those prescribed growth hormone (19,20). Therefore, although possible, it is unlikely that either the previous history of malignancy or the use of growth hormone were important predisposing factors for the development of HCC in our first patient, and this more strongly implicates HCV as the major oncogenic factor. It should also be emphasized that this patient received large doses of glucocorticosteroids after stem cell transplantation for the treatment of what was presumed to be graft-versus-host disease–related liver dysfunction. However, HCV tests were unavailable when she initially developed liver dysfunction, 2 months after stem cell transplantation. Therefore, this patient was likely infected with HCV during the transplant process. In retrospect, her liver problem was probably related to chronic HCV infection, which was diagnosed only years afterward, with the advent of virus-specific serological tests. Glucocorticoids are associated with accelerated progression of HCV disease in adults after liver transplantation (21,22) and, therefore, may have promoted the development of liver cancer in this adolescent. Furthermore, based on her family history of cancer, genetic factors may have contributed to the pathogenesis of liver cancer in our first patient. Risk factors associated with progression of liver disease in children with chronic HCV infection are poorly understood. In contrast to our first patient, patient 2 lacked comorbid conditions linked to progressive liver disease in children (23) and adults (24). Our second patient's mother was co-infected with HIV, which negatively affects the long-term clinical outcome in adults with HCV (25). However, patient 2 was not infected with HIV at the time of our evaluation, based on negative serological results for this virus. Nevertheless, it is plausible that in utero or perinatal exposure to HIV led to increased HCV heterogeneity, which is associated with higher serum transaminase levels in small pediatric studies (26,27). Although alcohol consumption, a predictor of ominous disease progression in adults with HCV (24), was not directly elicited in our adolescents, its occult use cannot be completely excluded and may have influenced the development of advanced disease in our patients. In all, the reasons underlying the accelerated rate of liver disease progression in our adolescents, particularly our second patient, remain unclear. Although treating children with HCV infection is challenging, our patients may have benefited from available antiviral therapy. However, HCV was diagnosed in our patients only after developing decompensated liver disease when antiviral treatment was deemed unsafe. Therefore, these adolescents underscore the importance of identifying HCV infection early and support careful serological screening of children at risk for this viral pathogen (28). Although hepatocellular carcinoma is rare in children, it is one of the most common primary liver tumors in this age group, accounting for approximately 20% to 30% of all such lesions (16,29). Indeed, HCC accounted for 87% of all primary liver tumors in adolescents (15–19 years old) reported to the National Center for Health Statistics between 1979 and 1996 (16). Interestingly, the cause of hepatocellular cancer was unknown in the vast majority of these cases. Because reliable serological tests to detect HCV were unavailable during most of the study period in this comprehensive report (16), it is possible that some of these cases of HCC may have been related to this viral infection, as occurred in our patients. Although our 2 patients succumbed to HCC, the outcome of this disease in childhood is not uniformly poor (30). The long-term survival of patients with liver cancer has improved in recent years with the advent of novel therapeutic techniques such as chemoablation and intratumor chemotherapeutic injections, in addition to tumor resection and liver transplantation (31). Favorable outcomes, however, generally correlate with smaller lesions, thus accentuating the need for early detection of HCC. Periodic monitoring of patients with HCV-related histological fibrosis or cirrhosis by serial serological assessment of AFP level and abdominal imaging may improve early diagnosis of liver cancer (32). These diagnostic methods are imperfect screening tools, as observed in our second patient, in whom HCC was detected only after histopathological evaluation of her explanted liver. Screening for HCC in children with chronic HCV infection is particularly difficult because development of tumor appears to be a rare complication in this unique group. At this time, there are no pediatric-specific guidelines to screen for HCC in children chronically infected with HCV. Those children presumably at greater risk (advanced fibrosis or cirrhosis) should undergo periodic surveillance (abdominal sonogram alone or with serum AFP determination every 6 to 12 months) as is currently recommended for adults (32). In conclusion, although HCV infection is an indolent disease in most infected children, potentially ominous sequelae including HCC can occur in the pediatric age group. Our patients highlight the critical importance of remaining vigilant for liver-related complications even in young patients with this viral pathogen.

WNTing no RASt for hepatocellular carcinoma.

Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

Acquisition of specific genetic alterations has been shown to play a pivotal role in the progression of various stages of liver cancer, and studies have proved that alteration of transforming growth factor-β (TGF-β) signaling pathway can lead to the development of gastrointestinal cancers including liver cancer. β-Spectrin (β2SP) is one of adapter proteins for Smad3/Smad4 complex formation during TGF-β signal transduction. Forty % of β2SP+/- mice develop liver cancer, and the underlying molecular mechanisms remain largely unclear. Hypothesis: Compared to wild-type (WT) mice, β2SP+/- mice had significantly higher number of inflammatory nodules in the liver and this pathological feature might be one of mechanisms contributing to liver cancer formation seen in β2SP+/- mice. Inflammation plays a crucial role at different stages of tumor development. We hypothesize that an increase in liver inflammation leads to liver cancer formation in β2SP+/- mice. We proposed to study the mechanism by which β2SP regulates liver inflammation and suppresses liver cancer development. Experimental Procedures and Results: (1) We dissected livers from 18-month-old WT and β2SP+/- mice and processed for paraffin embedding and the tissue slides were used for hematoxylin and eosin (H&amp;E) staining. We observed inflammatory nodules in the liver of near 60% β2SP+/- mice compared to less than 5% in WT mice. (2) To identify the type of leucocytes infiltrated in the liver tissues, we carried out immunohistochemistry staining by using antibodies directly against macrophage, T-cell receptor and B-cell antigen, and found that the number of T- and B-lymphocytes in the liver was significantly higher in β2SP+/- mice than that in WT mice. (3) Microarray and quantitative real-time RT-PCR analyses indicated that hepatic expression of interleukin-1 α (IL-1α) and IL-1β mRNA was highly upregulated only in β2SP+/- mice. (4) Western blot analyses showed that STAT3 activation in the liver was higher in β2SP+/- mice than that in WT mice. Double mutant mice with β2SP+/- and liver specific deletion of STAT3 (LSTAT3-/-) had reduced inflammatory nodules and IL-1 expression compared to β2SP+/- mice, suggesting that STAT3 is one of the regulators in mediating the cross-talk between β2SP and IL-1 in the regulation of inflammatory response in liver. Conclusion: Our results suggest that hepatic expression of IL-1α and IL-1β is induced in β2SP+/- mice, which is likely due to the elevated activation of STAT3 and contributes to the increased hepatic inflammation in β2SP+/- mice. Citation Format: Ling Lin, Hua Wang, Bin Gao, Xiuling Zhi, Aiwu Ruth He. Mechanistic analysis of liver inflammation and cancer formation in mice with heterozygous lose of β-spectrin (β2SP). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5184. doi:10.1158/1538-7445.AM2013-5184

Hepatocellular carcinoma without cirrhosis: think acute hepatic porphyrias and vice versa

Simple SummaryWe recently reported that the human TOR signaling regulator (hereafter TIPRL) contributes to the drug-resistance of hepatocellular carcinomas (HCCs) and the involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness. This study aims to determine prognostic and diagnostic efficacies of TIPRL/LC3/CD133/CD44 for early liver cancer. We observed the significant upregulation of TIPRL and LC3 in HCCs and adult hepatocyte-derived liver disease while observing downregulation in intrahepatic carcinomas (iCCA). The TIPRL level has been shown to be the clearest indicator of liver cancer patients’ survivability as a sole covariate. This indication supports that TIPRL contributed to liver cancer cell proliferation and survival via stemness and self-renewal induction. TIPRL/LC3/CD133 have exhibited crucial efficiency in diagnostic patients with grade 1 iCCA, and TIPRL/LC3/CD133/CD44 showed prognosticating grade-1 HCCs and iCCA, either as an alone or in conjunction. Overall, this study reports that TIPRL/LC3/CD133/CD44 could, either individually or in conjunction, serve as potential biomarkers for early liver cancer.Recently, we reported the involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness. This study assessed the human TOR signaling regulator (TIPRL)/microtubule-associated light chain 3 (LC3)/prominin-1 (CD133)/cluster of differentiation 44 (CD44) as potential diagnostic and prognostic biomarkers for early liver cancer. For the assessment, we stained tissues of human liver disease/cancer with antibodies against TIPRL/LC3/CD133/CD44/CD46, followed by confocal observation. The roles of TIPRL/LC3/CD133/CD44/CD46 in liver normal and cancer cell lines were determined by in vitro studies. We analyzed the prognostic and diagnostic potentials of TIPRL/LC3/CD133/CD44/CD46 using the receiver-operating characteristic curve, a Kaplan–Meier and uni-/multi-Cox analyses. TIPRL and LC3 were upregulated in tissues of HCCs and adult hepatocytes-derived liver diseases while downregulated in iCCA. Intriguingly, TIPRL levels were found to be critically associated with liver cancer patients’ survivability, and TIPRL is the key player in liver cancer cell proliferation and viability via stemness and self-renewal induction. Furthermore, we demonstrate that TIPRL/LC3/CD133 have shown prominent efficiency for diagnosing patients with grade 1 iCCA. TIPRL/LC3/CD133/CD44 have also provided excellent potential for prognosticating patients with grade 1 iCCA and grade 1 HCCs, together with demonstrating that TIPRL/LC3/CD133/CD44 are, either individually or in conjunction, potential biomarkers for early liver cancer.

Chapter 2: Diagnosis and surveillance