Among these 20 patients, HCC was located in the Spiegel lobe in eight patients, in the paracaval portion in another 10 and in the caudate process in two. We evaluated differences in the local recurrence rate and the incidence of complications associated with RFA between the caudate and the non-caudate groups. The 4-year cumulative

local recurrence rate after RFA in the caudate group and the non-caudate group was 22.3% and 4.5%, respectively (P < 0.001). Multivariate analysis of factors affecting local recurrence demonstrated that tumor size and tumor location (caudate or non-caudate) were independent significant factors. No postoperative Selleckchem Ruxolitinib complications were observed in the caudate group, whereas 15 patients (2.8%) in the non-caudate group experienced complications related to RFA. We were able to safely treat HCC located in the caudate lobe by RFA. However, there was a high incidence of local recurrence, presumably because of the heat sink effect of the inferior vena cava and the restricted puncture approach. We should pursue a revised method to reduce local recurrence. “
“We read with great interest the results that the expression of circulating microRNA (miRNA) miR-122 was substantially higher in acetaminophen-induced acute liver injury (APAP-ALI)

patients, compared to healthy controls, using quantitative real-time polymerase chain reaction (PCR) assays with U6 small nuclear RNA (snRNA) as an internal control, as reported by Starkey Lewis et al. 1 However, serum miRNA expression

BYL719 mouse profiles generated from a large number of human samples by our laboratory indicate that circulating U6 snRNA is not a reliable internal normalizer. The accuracy of circulating miRNA medchemexpress expression analysis critically depends on proper normalization of the data. Endogenous normalizer specific for circulating miRNAs have not yet been well defined. Although some cell/tissue miRNA normalizers, including U6 and miR-16, have been used in circulating miRNA data analyses, recent studies suggest that cell/tissue normalizers may not serve as circulating normalizers. 2 To identify the miRNAs with the most stable expression in human serum, we have evaluated 117 serum miRNA expression profiles from young, aging, and different disease conditions using a real-time PCR array system, based on a global expression mean normalization strategy. 3 Of 332 miRNAs detected in serum, 58 displayed consistent expression across all samples (Fig. 1A). Our criteria to identify ideal circulating miRNA normalizers includes (1) no statistical difference among all groups, (2) the smallest variation across all samples (standard deviation of |−ΔCT| < 1); and (3) relative high expression, closest to the global mean expression. 3 Three miRNAs, miR-374a, miR-374b, and let-7d, met all criteria (Fig.

In the c-Myc/Tgfα transgenic model, MHC-1 is down-regulated and Rae1 is up-regulated on dysplastic hepatocytes targeting them for NK surveillance. However, malignant progression still succeeds, presumably due to insufficient NK numbers.49 NKT cells significantly increased in c-Myc/Tgfα dysplastic liver as it progressed toward

malignancy. Distinct NKT cell subsets can either promote (CD4+ NKT) or inhibit (iNKT) liver cancer50 (recently reviewed by Subleski et al.51) and can partially explain this observation. Bridging innate and adaptive immune systems, resident DCs are less functional in liver, JNK activity but are still capable of priming antiviral T-cell responses sufficient for clearance. Upon viral escape, chronic liver inflammation renders liver DCs suppressed, as observed in chronically infected HCV patients showing a diminished ability to mature and prime T-cell proliferation and induce IFN-γ.52 Interaction between HCV core protein and DCs in culture results in reduced frequency

of pDC and direct inhibition of IFNα production.53 Core protein can also inhibit IL-12 production by DCs through an intracellular mechanism dependent on a combination of TLR4 signaling and cross-linking of the complement receptor,54 thereby contributing to a Th2 skewed microenvironment. HBV-infected patients have diminished pDC functions resulting in part from a specific HBV antigen (HBeAg).55 These findings suggest persistent viral infection and chronic inflammation deprive DC’s ability to prime T-cell surveillance, augmenting hepatocellular carcinogenesis. http://www.selleckchem.com/products/cx-5461.html 上海皓元 Circulating B cells from cirrhosis patients have been reported to be hyporesponsive to ex vivo CD40/TLR9 stimulation, as characterized by LTα secretion, IgG production, and T-cell allostimulation. A reduction in CD27+IgM+ memory B cells was also observed in cirrhosis patients.56 These changes support a reduced B-cell-mediated antiviral response, allowing persistent viral infection, associated inflammation, and HCC development. In contrast, results from an inflammatory skin model of HPV16 squamous cell carcinomas (SCC) suggest a more direct, tumor-promoting role for B cells, possibly by way of immunoglobulin

accumulation.57 Although controversial, increased levels of immunoglobulin in murine HCC models, serum from cirrhotic individuals, and HCC lesions58 all suggest a possible cause-and-effect linkage between the presence of immunoglobulin and HCC development. Previously, we established a murine de novo liver tumor model of adenoma and carcinoma by hydrodynamic injection of transposons containing myrAKT (AKT) and Δ90 β-catenin (β-CAT).59 We observed hepatocellular tumor development/progression to be largely dependent on B cells (authors’ unpubl. obs.). We also found that tumor infiltrating B cells express elevated levels of TNF-α (authors’ unpubl. obs.), suggesting that B cell-derived cytokines could be instrumental in tumor development/progression.

In the c-Myc/Tgfα transgenic model, MHC-1 is down-regulated and Rae1 is up-regulated on dysplastic hepatocytes targeting them for NK surveillance. However, malignant progression still succeeds, presumably due to insufficient NK numbers.49 NKT cells significantly increased in c-Myc/Tgfα dysplastic liver as it progressed toward

malignancy. Distinct NKT cell subsets can either promote (CD4+ NKT) or inhibit (iNKT) liver cancer50 (recently reviewed by Subleski et al.51) and can partially explain this observation. Bridging innate and adaptive immune systems, resident DCs are less functional in liver, Veliparib datasheet but are still capable of priming antiviral T-cell responses sufficient for clearance. Upon viral escape, chronic liver inflammation renders liver DCs suppressed, as observed in chronically infected HCV patients showing a diminished ability to mature and prime T-cell proliferation and induce IFN-γ.52 Interaction between HCV core protein and DCs in culture results in reduced frequency

of pDC and direct inhibition of IFNα production.53 Core protein can also inhibit IL-12 production by DCs through an intracellular mechanism dependent on a combination of TLR4 signaling and cross-linking of the complement receptor,54 thereby contributing to a Th2 skewed microenvironment. HBV-infected patients have diminished pDC functions resulting in part from a specific HBV antigen (HBeAg).55 These findings suggest persistent viral infection and chronic inflammation deprive DC’s ability to prime T-cell surveillance, augmenting hepatocellular carcinogenesis. selleck MCE公司 Circulating B cells from cirrhosis patients have been reported to be hyporesponsive to ex vivo CD40/TLR9 stimulation, as characterized by LTα secretion, IgG production, and T-cell allostimulation. A reduction in CD27+IgM+ memory B cells was also observed in cirrhosis patients.56 These changes support a reduced B-cell-mediated antiviral response, allowing persistent viral infection, associated inflammation, and HCC development. In contrast, results from an inflammatory skin model of HPV16 squamous cell carcinomas (SCC) suggest a more direct, tumor-promoting role for B cells, possibly by way of immunoglobulin

accumulation.57 Although controversial, increased levels of immunoglobulin in murine HCC models, serum from cirrhotic individuals, and HCC lesions58 all suggest a possible cause-and-effect linkage between the presence of immunoglobulin and HCC development. Previously, we established a murine de novo liver tumor model of adenoma and carcinoma by hydrodynamic injection of transposons containing myrAKT (AKT) and Δ90 β-catenin (β-CAT).59 We observed hepatocellular tumor development/progression to be largely dependent on B cells (authors’ unpubl. obs.). We also found that tumor infiltrating B cells express elevated levels of TNF-α (authors’ unpubl. obs.), suggesting that B cell-derived cytokines could be instrumental in tumor development/progression.

Accordingly, silencing of the PLK3 gene triggered hepatocarcinogenesis in a mouse model.18 Moreover, we frequently found LOH for the PLK4 gene in many HCC samples, with the highest incidence in HCCP. The PLK4 locus is located at the chromosomal band 4q28.1, which is frequently affected by LOH in HCC and whose crucial role in liver carcinogenesis has been envisaged.36, 37 In accordance with the latter

hypothesis, PLK4 heterozygosity resulted in spontaneous liver tumor development in a mouse model, which was associated with centrosome amplification and induction of chromosomal instability19 as characteristically observed in human Protease Inhibitor Library HCC.37, 38 Thus, PLK4 might be one of the pivotal tumor suppressor genes located in the 4q28.1 chromosome region,

whose loss contributes to human hepatocarcinogenesis. Furthermore, we have investigated in more detail the role of PLK1 on cell cycle regulation in human HCC cell lines. Our data confirm the important function of PLK1 in regulating both the G2/M phase of the cell cycle and the apoptotic process, supporting previous observations in various cancer cell lines.25, 39, 40 In particular, the present findings indicate that PLK1 is able to inhibit apoptosis in a p53 family–dependent manner, as observed in Hep3B and HepG2 cell lines. It has been demonstrated that PLK1 interacts with the DNA binding domain of p53, thereby decreasing its stability and transcriptional activity.26 The latter mechanism might explain PARP inhibitor cancer the increased apoptosis rate reported in HepG2 cells (p53 wild-type) with subsequent down-regulation of antiapoptotic proteins following PLK1 silencing. Recently, a physical interaction between PLK1 and p73, another member of the p53 family, has been demonstrated in different cell lines.27, 28 Like p53, p73 transactivates many p53 target genes involved in cell cycle control and apoptosis. PLK1 is able to phosphorylate p73 at the threonine 27 residue within its transactivation domain, thereby abrogating its transcriptional activity.27, MCE 28 We detected an increase in p73 protein level and its target genes following silencing of PLK1

expression in Hep3B and HepG2 cells. Up-regulation of the p73 protein was also observed in MCF7 breast cancer cells expressing the p53 gene,27 confirming that p73 induction by PLK1 is independent of p53 in different cellular contexts. In a recent report, a therapeutic approach using a PLK1 inhibitor resulted in dramatic tumor regression in nude mice bearing xenografts of HCT116 colorectal cancer cells in which the p53 gene was disrupted, suggesting a crucial function of PLK1 for the growth of p53-deficient tumor cells.41 Similarly, we show here that the growth of SNU-182 cells overexpressing Ha-Ras, FOXM1, and PLK1 is dramatically reduced and impaired when this axis is disrupted by either FOXM1 or PLK1 suppression through siRNA in vitro (Fig. 7D).

Accordingly, silencing of the PLK3 gene triggered hepatocarcinogenesis in a mouse model.18 Moreover, we frequently found LOH for the PLK4 gene in many HCC samples, with the highest incidence in HCCP. The PLK4 locus is located at the chromosomal band 4q28.1, which is frequently affected by LOH in HCC and whose crucial role in liver carcinogenesis has been envisaged.36, 37 In accordance with the latter

hypothesis, PLK4 heterozygosity resulted in spontaneous liver tumor development in a mouse model, which was associated with centrosome amplification and induction of chromosomal instability19 as characteristically observed in human Copanlisib HCC.37, 38 Thus, PLK4 might be one of the pivotal tumor suppressor genes located in the 4q28.1 chromosome region,

whose loss contributes to human hepatocarcinogenesis. Furthermore, we have investigated in more detail the role of PLK1 on cell cycle regulation in human HCC cell lines. Our data confirm the important function of PLK1 in regulating both the G2/M phase of the cell cycle and the apoptotic process, supporting previous observations in various cancer cell lines.25, 39, 40 In particular, the present findings indicate that PLK1 is able to inhibit apoptosis in a p53 family–dependent manner, as observed in Hep3B and HepG2 cell lines. It has been demonstrated that PLK1 interacts with the DNA binding domain of p53, thereby decreasing its stability and transcriptional activity.26 The latter mechanism might explain selleck compound the increased apoptosis rate reported in HepG2 cells (p53 wild-type) with subsequent down-regulation of antiapoptotic proteins following PLK1 silencing. Recently, a physical interaction between PLK1 and p73, another member of the p53 family, has been demonstrated in different cell lines.27, 28 Like p53, p73 transactivates many p53 target genes involved in cell cycle control and apoptosis. PLK1 is able to phosphorylate p73 at the threonine 27 residue within its transactivation domain, thereby abrogating its transcriptional activity.27, MCE 28 We detected an increase in p73 protein level and its target genes following silencing of PLK1

expression in Hep3B and HepG2 cells. Up-regulation of the p73 protein was also observed in MCF7 breast cancer cells expressing the p53 gene,27 confirming that p73 induction by PLK1 is independent of p53 in different cellular contexts. In a recent report, a therapeutic approach using a PLK1 inhibitor resulted in dramatic tumor regression in nude mice bearing xenografts of HCT116 colorectal cancer cells in which the p53 gene was disrupted, suggesting a crucial function of PLK1 for the growth of p53-deficient tumor cells.41 Similarly, we show here that the growth of SNU-182 cells overexpressing Ha-Ras, FOXM1, and PLK1 is dramatically reduced and impaired when this axis is disrupted by either FOXM1 or PLK1 suppression through siRNA in vitro (Fig. 7D).

The Peripheral Regulation.— Expansion of adipose tissue during weight gain leads to the recruitment of macrophages and T-cells, as well as changes in the synthesis of cytokines and adipocytokine by adipocytes.36 Specifically, weight gain leads to the induction of adipocytokines and several pro-inflammatory cytokines, including TNF-α, IL-1, and IL-6; all of which can contribute to local and systemic inflammation (Fig. 2).36,72 In the next section we will briefly review

the role of cytokines in feeding and their link to migraine. Cytokines.— Pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α, are proteins that are predominantly produced by activated immune cells and are involved in amplification of the inflammatory response. Interleukin-6, IL-10,

and TNF-α are also expressed or modulated by adipocytes.37 The extent to which adipocytes modulates their activity varies based on body fat. Small molecule library For example TNF-α is mainly produced by macrophages; and with the increase in resident adipose tissue macrophages with obesity, this results in the main source of TNF-α coming from adipose tissue macrophages. TNF-α has also been shown to induce insulin resistance and inhibit adipocyte differentiation.56 Similarly one-third of the IL-6 concentration in the circulation of obese individuals selleck chemical comes from adipocytes.37,60 Several alterations in cytokines have been reported in patients with migraine. Specifically, serum TNF-α and IL-6 have been shown to be increased ictally in episodic migraineurs, while increased cerebrospinal fluid TNF-α has been demonstrated in chronic daily headache sufferers.73,74 In addition, serum levels of the anti-inflammatory cytokine, IL-10 have also been shown to be lower following treatment of acute attacks with sumatriptan, suggesting elevated levels

of IL-10 during acute attacks.75 Adiponectin and leptin have been shown to be modulated and to modulate several of these cytokines. Thus, future studies evaluating the effect of cytokines on adipocytokines and of adipocytokines on cytokines in migraineurs would be of interest. Adipose tissue is a dynamic neuroendocrine organ that participates in multiple physiological and pathological processes, including inflammation.48 Clinical, population-based, translational, and basic science research show MCE multiple areas of overlap between the central and peripheral pathways regulating feeding and migraine pathophysiology. The current epidemiological research suggests that chronic daily headache prevalence is increased in adults with obesity and that the prevalence of episodic headaches may be increased in reproductive-aged adults with obesity as well. In order to define this relationship more fully, future studies should use standardized methods to estimate obesity and migraine. Further, the gender- and age-related changes of both obesity and migraine should be taken into account.

The Peripheral Regulation.— Expansion of adipose tissue during weight gain leads to the recruitment of macrophages and T-cells, as well as changes in the synthesis of cytokines and adipocytokine by adipocytes.36 Specifically, weight gain leads to the induction of adipocytokines and several pro-inflammatory cytokines, including TNF-α, IL-1, and IL-6; all of which can contribute to local and systemic inflammation (Fig. 2).36,72 In the next section we will briefly review

the role of cytokines in feeding and their link to migraine. Cytokines.— Pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α, are proteins that are predominantly produced by activated immune cells and are involved in amplification of the inflammatory response. Interleukin-6, IL-10,

and TNF-α are also expressed or modulated by adipocytes.37 The extent to which adipocytes modulates their activity varies based on body fat. Small molecule library cost For example TNF-α is mainly produced by macrophages; and with the increase in resident adipose tissue macrophages with obesity, this results in the main source of TNF-α coming from adipose tissue macrophages. TNF-α has also been shown to induce insulin resistance and inhibit adipocyte differentiation.56 Similarly one-third of the IL-6 concentration in the circulation of obese individuals find more comes from adipocytes.37,60 Several alterations in cytokines have been reported in patients with migraine. Specifically, serum TNF-α and IL-6 have been shown to be increased ictally in episodic migraineurs, while increased cerebrospinal fluid TNF-α has been demonstrated in chronic daily headache sufferers.73,74 In addition, serum levels of the anti-inflammatory cytokine, IL-10 have also been shown to be lower following treatment of acute attacks with sumatriptan, suggesting elevated levels

of IL-10 during acute attacks.75 Adiponectin and leptin have been shown to be modulated and to modulate several of these cytokines. Thus, future studies evaluating the effect of cytokines on adipocytokines and of adipocytokines on cytokines in migraineurs would be of interest. Adipose tissue is a dynamic neuroendocrine organ that participates in multiple physiological and pathological processes, including inflammation.48 Clinical, population-based, translational, and basic science research show medchemexpress multiple areas of overlap between the central and peripheral pathways regulating feeding and migraine pathophysiology. The current epidemiological research suggests that chronic daily headache prevalence is increased in adults with obesity and that the prevalence of episodic headaches may be increased in reproductive-aged adults with obesity as well. In order to define this relationship more fully, future studies should use standardized methods to estimate obesity and migraine. Further, the gender- and age-related changes of both obesity and migraine should be taken into account.

Infusions of conventional factor VIII concentrates are unlikely to be of any value in patients with inhibitor titres above 5 BU. Bypassing agents induce thrombin formation

on the surface of platelets in the absence of either factor VIII or IX. There are advantages and disadvantages with both the available licensed products. FEIBA (Baxter) is a plasma-derived prothrombin complex concentrate (PCC), which is subjected to heat treatment and nanofiltration. The duration of action of FEIBA is in the range of 6–9 h. rFVIIa is a recombinant product with a half-life of around 3 h. The use of rFVIIa does not provoke an anamnestic rise in antibody titre, which can occur in association with the administration of FEIBA, as the latter contains traces of factor VIII. Thrombotic complications have BGJ398 been reported with both FEIBA and rFVIIa, although the absolute risk seems arguably lower with rFVIIa with a reported incidence of around 4/100 000 infusions [4,5]. selleck chemicals llc The production of inhibitory antibodies can be suppressed in many cases through the administration of high doses of coagulation factor over long periods, often up to 2 years (“immune tolerance”) [6,7]. Predictors of a successful outcome include a low initial antibody titre (<10 BU), a low historical

peak inhibitor titre, and an early institution of treatment (an interval of less than 2 years between inhibitor diagnosis and initiation of immune tolerance). It is pointless to attempt immune tolerance 上海皓元 in an adult who has had high-titre antibody for many years, and interruption of treatment may also have an adverse effect. The treatment is very expensive and also demanding for the child and family, and in many cases it is necessary to insert an indwelling central venous line (Port-A-Cath or similar device), which also entails risks of bacterial infection and/or thrombosis. The dosage utilized for immune tolerance remains a subject of controversy, and various groups have used doses in the range of 50–200 IU/kg/day. Overall, the response rate with the various current regimes is of the order of 85% and the relapse is fortunately

rare in successful cases. Inhibitor development in haemophilia B is an uncommon phenomenon but the antibodies often retain the ability to fix complement, and serious allergic reactions may develop after infusions [6]. Such a reaction may be the very first manifestation of inhibitor development. It is generally felt that recombinant activated factor VII (rVIIa, NovoSeven) is the best option for further treatment. The use of activated prothrombin complex concentrates, such as FEIBA, should be avoided as these contain significant amounts of factor IX. Conventional immune tolerance has a significantly lower chance of success in haemophilia A. The development of nephrotic syndrome has also been reported in such patients. A number of new products are under development.

Infusions of conventional factor VIII concentrates are unlikely to be of any value in patients with inhibitor titres above 5 BU. Bypassing agents induce thrombin formation

on the surface of platelets in the absence of either factor VIII or IX. There are advantages and disadvantages with both the available licensed products. FEIBA (Baxter) is a plasma-derived prothrombin complex concentrate (PCC), which is subjected to heat treatment and nanofiltration. The duration of action of FEIBA is in the range of 6–9 h. rFVIIa is a recombinant product with a half-life of around 3 h. The use of rFVIIa does not provoke an anamnestic rise in antibody titre, which can occur in association with the administration of FEIBA, as the latter contains traces of factor VIII. Thrombotic complications have Bafilomycin A1 supplier been reported with both FEIBA and rFVIIa, although the absolute risk seems arguably lower with rFVIIa with a reported incidence of around 4/100 000 infusions [4,5]. PKC412 ic50 The production of inhibitory antibodies can be suppressed in many cases through the administration of high doses of coagulation factor over long periods, often up to 2 years (“immune tolerance”) [6,7]. Predictors of a successful outcome include a low initial antibody titre (<10 BU), a low historical

peak inhibitor titre, and an early institution of treatment (an interval of less than 2 years between inhibitor diagnosis and initiation of immune tolerance). It is pointless to attempt immune tolerance MCE公司 in an adult who has had high-titre antibody for many years, and interruption of treatment may also have an adverse effect. The treatment is very expensive and also demanding for the child and family, and in many cases it is necessary to insert an indwelling central venous line (Port-A-Cath or similar device), which also entails risks of bacterial infection and/or thrombosis. The dosage utilized for immune tolerance remains a subject of controversy, and various groups have used doses in the range of 50–200 IU/kg/day. Overall, the response rate with the various current regimes is of the order of 85% and the relapse is fortunately

rare in successful cases. Inhibitor development in haemophilia B is an uncommon phenomenon but the antibodies often retain the ability to fix complement, and serious allergic reactions may develop after infusions [6]. Such a reaction may be the very first manifestation of inhibitor development. It is generally felt that recombinant activated factor VII (rVIIa, NovoSeven) is the best option for further treatment. The use of activated prothrombin complex concentrates, such as FEIBA, should be avoided as these contain significant amounts of factor IX. Conventional immune tolerance has a significantly lower chance of success in haemophilia A. The development of nephrotic syndrome has also been reported in such patients. A number of new products are under development.

In the present study we found that LPCs survived long-term TGF-β treatment and underwent neoplastic transformation and exhibited T-IC characteristics. It has been well established that TGF-β levels are notably increased in cirrhotic liver and compensatory proliferation of LPCs during cirrhosis preceding HCC is secondary to sustained liver injury. Our results presented here suggest the chronic and progressively enhanced transforming effect of TGF-β on LPCs in the context of sustained liver damage. Maintenance and proliferation of stem/progenitor cells are tightly regulated by comprehensive

Venetoclax manufacturer signaling network involving JAK/STAT3, NOTCH, PTEN, Akt/FOXO3a, etc.46 Dysregulation of these pathways may lead to aberrant proliferation or neoplastic transition of stem/progenitor cells. With this report, we unveiled that long-term TGF-β exposure down-regulated PTEN expression and up-regulated Akt phosphorylation in LPCs, which subsequently led to the nuclear exportation Dinaciclib of FOXO3a and neoplastic transformation of LPCs. FOXO transcription factors participate in a variety of cellular events including the maintenance of cell differentiation.47 The FOXO family

consists of four members: FOXO1, FOXO3a, FOXO4, and FOXO6, and functions in the nucleus of the cell. FOXO3a has been considered the key mediator for the maintenance of hematopoietic stem cells and the nuclear exportation of FOXO3a by phosphorylated Akt was proved to be a critical event during the transformation of stem/progenitor cells.28, 48 In the current study, our data indicate that Akt is responsible for FOXO3a inactivation and T-ICs generation in LPCs exposed to TGF-β. Akt phosphorylation is usually enhanced as a consequence of PI3-K activation or PTEN suppression.49 In the present study, PTEN suppression but not PI3-K activation was observed in LPCs upon long-term TGF-β treatment. Dysfunction of PTEN has been widely detected in various cancers and accumulating studies have implicated the pivotal role of PTEN in the maintenance of stem cells.50, 51 Impaired PTEN function could induce the transformation of stem cells into

上海皓元医药股份有限公司 cancer stem cells, sequentially initiating tumorigenesis. Fu et al.52 reported that PTEN deficiency in mice and zebrafish induced myelodysplasia with aberrant infiltration of myeloid progenitor cells. Enhancement of PTEN signaling not only depleted leukemia-initiating cells but also restored normal HSC function, which indicates the regulatory mechanistic difference between normal stem cells and cancer stem cells, and suggests that PTEN might be pharmaceutically targeted to deplete cancer stem cells without damaging normal stem cells.53 Herein, our data also indicate that PTEN is an indispensable moderator for LPC maintenance and is significantly reduced in hepatic T-ICs. Therefore, molecular therapy targeting PTEN might be a promising approach for HCC therapy.