NAD(P)H Quinone Dehydrogenase 1 Ablation Inhibits Activation of the Phosphoinositide 3-Kinase/Akt Serine/Threonine Kinase and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathways and Blocks Metabolic Adaptation in Hepatocellular Carcinoma.

Cancer cells undergo metabolic adaptation to sustain uncontrolled proliferation. Aerobic glycolysis and glutaminolysis are two of the most essential characteristics of cancer metabolic reprogramming. Hyperactivated phosphoinositide 3-kinase (PI3K)/Akt serine/threonine kinase (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways play central roles in cancer cell metabolic adaptation given that their downstream effectors, such as Akt and c-Myc, control most of the glycolytic and glutaminolysis genes. Here, we report that the cytosolic flavoprotein, NAD(P)H quinone dehydrogenase 1 (Nqo1), is strongly overexpressed in mouse and human hepatocellular carcinoma (HCC). Knockdown of Nqo1 enhanced activity of the serine/threonine phosphatase, protein phosphatase 2A, which operates at the intersection of the PI3K/Akt and MAPK/ERK pathways and dephosphorylates and inactivates pyruvate dehydrogenase kinase 1, Akt, Raf, mitogen-activated protein kinase kinase, and ERK1/2. Nqo1 ablation also induced the expression of phosphatase and tensin homolog, a dual protein/lipid phosphatase that blocks PI3K/Akt signaling, through the ERK/cAMP-responsive element-binding protein/c-Jun pathway. Together, Nqo1 ablation triggered simultaneous inhibition of the PI3K/Akt and MAPK/ERK pathways, suppressed the expression of glycolysis and glutaminolysis genes and blocked metabolic adaptation in liver cancer cells. Conversely, Nqo1 overexpression caused hyperactivation of the PI3K/Akt and MAPK/ERK pathways and promoted metabolic adaptation. Conclusion: In conclusion, Nqo1 functions as an upstream activator of both the PI3K/Akt and MAPK/ERK pathways in liver cancer cells, and Nqo1 ablation blocked metabolic adaptation and inhibited liver cancer cell proliferation and HCC growth in mice. Therefore, our results suggest that Nqo1 may function as a therapeutic target to inhibit liver cancer cell proliferation and inhibit HCC.

Speedy A-Cdk2 binding mediates initial telomere-nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation.

Telomere attachment to the nuclear envelope (NE) is a prerequisite for chromosome movement during meiotic prophase I that is required for pairing of homologous chromosomes, synapsis, and homologous recombination. Here we show that Speedy A, a noncanonical activator of cyclin-dependent kinases (Cdks), is specifically localized to telomeres in prophase I male and female germ cells in mice, and plays an essential role in the telomere-NE attachment. Deletion of Spdya in mice disrupts telomere-NE attachment, and this impairs homologous pairing and synapsis and leads to zygotene arrest in male and female germ cells. In addition, we have identified a telomere localization domain on Speedy A covering the distal N terminus and the Cdk2-binding Ringo domain, and this domain is essential for the localization of Speedy A to telomeres. Furthermore, we found that the binding of Cdk2 to Speedy A is indispensable for Cdk2's localization on telomeres, suggesting that Speedy A and Cdk2 might be the initial components that are recruited to the NE for forming the meiotic telomere complex. However, Speedy A-Cdk2-mediated telomere-NE attachment is independent of Cdk2 activation. Our results thus indicate that Speedy A and Cdk2 might mediate the initial telomere-NE attachment for the efficient assembly of the telomere complex that is essential for meiotic prophase I progression.

The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting.

Cachexia is a complex tissue-wasting syndrome characterized by inflammation, hypermetabolism, increased energy expenditure, and anorexia. Browning of white adipose tissue (WAT) is one of the significant factors that contribute to energy wasting in cachexia. By utilizing a cell implantation model, we demonstrate here that the lipid mobilizing factor zinc-α2-glycoprotein (ZAG) induces WAT browning in mice. Increased circulating levels of ZAG not only induced lipolysis in adipose tissues but also caused robust browning in WAT. Stimulating WAT progenitors with ZAG recombinant protein or expression of ZAG in mouse embryonic fibroblasts (MEFs) strongly enhanced brown-like differentiation. At the molecular level, ZAG stimulated peroxisome proliferator-activated receptor γ (PPARγ) and early B cell factor 2 expression and promoted their recruitment to the PR/SET domain 16 (Prdm16) promoter, leading to enhanced expression of Prdm16, which determines brown cell fate. In brown adipose tissue, ZAG stimulated the expression of PPARγ and PPARγ coactivator 1α and promoted recruitment of PPARγ to the uncoupling protein 1 (Ucp1) promoter, leading to increased expression of Ucp1. Overall, our results reveal a novel function of ZAG in WAT browning and highlight the targeting of ZAG as a potential therapeutic application in humans with cachexia.-Elattar, S., Dimri, M., Satyanarayana, A. The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting.

Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells.

Reprograming of metabolism is one of the central hallmarks of cancer. The majority of cancer cells depend on high rates of glycolysis and glutaminolysis for their growth and survival. A number of oncogenes and tumor suppressors have been connected to the regulation of altered glucose and glutamine metabolism in cancer cells. For example, the oncogene c-Myc plays vital roles in cancer cell metabolic adaptation by directly regulating various genes that participate in aerobic glycolysis and glutaminolysis. Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays important roles in cell proliferation, differentiation, and cell fate determination. Overexpression of Id1 causes intestinal adenomas and thymic lymphomas in mice, suggesting that Id1 could function as an oncogene. Despite it being an oncogene, whether Id1 plays any prominent role in cancer cell metabolic reprograming is unknown. Here, we demonstrate that Id1 is strongly expressed in human and mouse liver tumors and in hepatocellular carcinoma (HCC) cell lines, whereas its expression is very low or undetectable in normal liver tissues. In HCC cells, Id1 expression is regulated by the MAPK/ERK pathway at the transcriptional level. Knockdown of Id1 suppressed aerobic glycolysis and glutaminolysis, suggesting that Id1 promotes a metabolic shift toward aerobic glycolysis. At the molecular level, Id1 mediates its metabolic effects by regulating the expression levels of c-Myc. Knockdown of Id1 resulted in down-regulation (∼75%) of c-Myc, whereas overexpression of Id1 strongly induced (3-fold) c-Myc levels. Interestingly, knockdown of c-Myc resulted in down-regulation (∼60%) of Id1, suggesting a positive feedback-loop regulatory mechanism between Id1 and c-Myc. Under anaerobic conditions, both Id1 and c-Myc are down-regulated (50-70%), and overexpression of oxygen-insensitive hypoxia-inducible factor 1α (Hif1α) or its downstream target Mxi1 resulted in a significant reduction of c-Myc and Id1 (∼70%), suggesting that Hif1α suppresses Id1 and c-Myc under anaerobic conditions via Mxi1. Together, our findings indicate a prominent novel role for Id1 in liver cancer cell metabolic adaptation.

Can Brown Fat Win the Battle Against White Fat?

A rapid growth in the overweight and obese population in the last few decades suggest that the current diet, exercise, awareness or drug strategies are still not effectively restraining the obesity epidemic. Obesity results from increased energy intake, and the body's energy balance shifts towards energy abundance. Therefore, current research is focused on developing new strategies aimed at increasing energy expenditure. As a result, brown adipose tissue (BAT) is receiving tremendous attention since the major function of BAT is to dissipate energy as heat. For example, mouse models that have increased BAT activity or increased numbers of brown-like adipocytes within the white adipose tissue (WAT) are lean and protected from obesity. Alternatively, mouse models that lack BAT activity are more susceptible to age and diet-induced obesity. However, a significant loss of BAT mass during the natural growth process in humans has created enormous challenges in effectively utilizing this tissue to increase energy expenditure. New strategies are primarily focused on expanding the BAT mass and/or activating the existing BAT. In this regard, recent finding that expression of early B cell factor-2 (Ebf2) reprograms the white pre-adipocytes into brown adipocytes is a significant break-through in developing BAT-mediated strategies to treat obesity. Here we review the major biological functions of WAT and BAT, which play critical but opposing roles in the energy spectrum, energy storage versus energy expenditure, and we evaluate whether activation and/or expansion of BAT is practically achievable to treat obesity in humans.

Negative regulators of brown adipose tissue (BAT)-mediated thermogenesis.

Brown adipose tissue (BAT) is specialized for energy expenditure, a process called adaptive thermogenesis. PET-CT scans recently demonstrated the existence of metabolically active BAT in adult humans, which revitalized our interest in BAT. Increasing the amount and/or activity of BAT holds tremendous promise for the treatment of obesity and its associated diseases. PGC1α is the master regulator of UCP1-mediated thermogenesis in BAT. A number of proteins have been identified to influence thermogenesis either positively or negatively through regulating the expression or transcriptional activity of PGC1α. Therefore, BAT activation can be achieved by either inducing the expression of positive regulators of PGC1α or by inhibiting the repressors of the PGC1α/UCP1 pathway. Here, we review the most important negative regulators of PGC1α/UCP1 signaling and their mechanism of action in BAT-mediated thermogenesis.

Ablation of the transcriptional regulator Id1 enhances energy expenditure, increases insulin sensitivity, and protects against age and diet induced insulin resistance, and hepatosteatosis.

Obesity is a major health concern that contributes to the development of diabetes, hyperlipidemia, coronary artery disease, and cancer. Id proteins are helix-loop-helix transcription factors that regulate the proliferation and differentiation of cells from multiple tissues, including adipocytes. We screened mouse tissues for the expression of Id1 and found that Id1 protein is highly expressed in brown adipose tissue (BAT) and white adipose tissue (WAT), suggesting a role for Id1 in adipogenesis and cell metabolism. Id1(-/-) mice are viable but show a significant reduction in fat mass (P<0.005) over the life of the animal that was not due to decreased number of adipocytes. Analysis of Id1(-/-) mice revealed higher energy expenditure, increased lipolysis, and fatty acid oxidation, resulting in reduced triglyceride accumulation in WAT compared to Id1(+/+) mice. Serum levels of triglycerides (193.9±32.2 vs. 86.5±33.8, P<0.0005), cholesterol (189.4±33.8 vs. 110.6±8.23, P<0.0005) and leptin (1263±835 vs. 222±260, P<0.005) were significantly lower in aged Id1(-/-) mice compared to Id1(+/+) mice. Id1-deficient mice have higher resting (P<0.005) and total (P<0.05) O(2) consumption and lower respiratory exchange ratio (P<0.005), confirming that Id1(-/-) mice use a higher proportion of lipid as an energy source for the increased energy expenditure. The expression of PGC1α and UCP1 were 2- to 3-fold up-regulated in Id1(-/-) BAT, suggesting that loss of Id1 increases thermogenesis. As a consequence of higher energy expenditure and reduced fat mass, Id1(-/-) mice displayed enhanced insulin sensitivity. Id1 deficiency protected mice against age- and high-fat-diet-induced adiposity, insulin resistance, and hepatosteatosis. Our findings suggest that Id1 plays a critical role in the regulation of energy homeostasis and could be a potential target in the treatment of insulin resistance and fatty liver disease.

RapGEF2 is essential for embryonic hematopoiesis but dispensable for adult hematopoiesis.

RapGEF2 is one of many guanine nucleotide exchange factors (GEFs) that specifically activate Rap1. Here, we generated RapGEF2 conditional knockout mice and studied its role in embryogenesis and fetal as well as adult hematopoietic stem cell (HSC) regulation. RapGEF2 deficiency led to embryonic lethality at ~ E11.5 due to severe yolk sac vascular defects. However, a similar number of Flk1(+) cells were present in RapGEF2(+/+) and RapGEF2(-/-) yolk sacs indicating that the bipotential early progenitors were in fact generated in the absence of RapGEF2. Further analysis of yolk sacs and embryos revealed a significant reduction of CD41 expressing cells in RapGEF2(-/-) genotype, suggesting a defect in the maintenance of definitive hematopoiesis. RapGEF2(-/-) cells displayed defects in proliferation and migration, and the in vitro colony formation ability of hematopoietic progenitors was also impaired. At the molecular level, Rap1 activation was impaired in RapGEF2(-/-) cells that in turn lead to defective B-raf/ERK signaling. Scl/Gata transcription factor expression was significantly reduced, indicating that the defects observed in RapGEF2(-/-) cells could be mediated through Scl/Gata deregulation. Inducible deletion of RapGEF2 during late embryogenesis in RapGEF2(cko/cko)ER(cre) mice leads to defective fetal liver erythropoiesis. Conversely, inducible deletion in the adult bone marrow, or specific deletion in B cells, T cells, HSCs, and endothelial cells has no impact on hematopoiesis.

Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/ß-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development.

p16 and ARF: activation of teenage proteins in old age.

Cellular senescence induced by different stresses and telomere shortening appears to play an important role in the aging process. The products of the INK4a/ARF locus--p16INK4a and ARF--arrest cell proliferation at the senescence stage by exerting their effects on retinoblastoma protein- and p53-mediated responsive pathways. A study in this issue of the JCI provides experimental evidence of a specific upregulation of these cell cycle inhibitors in a variety of organs during mammalian aging.

Id1 Promotes Obesity by Suppressing Brown Adipose Thermogenesis and White Adipose Browning.

Obesity results from increased energy intake or defects in energy expenditure. Brown adipose tissue (BAT) is specialized for energy expenditure, a process called adaptive thermogenesis. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) controls BAT-mediated thermogenesis by regulating the expression of Ucp1 Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays an important role in cell proliferation and differentiation. We demonstrate a novel function of Id1 in BAT thermogenesis and programming of beige adipocytes in white adipose tissue (WAT). We found that adipose tissue-specific overexpression of Id1 causes age-associated and high-fat diet-induced obesity in mice. Id1 suppresses BAT thermogenesis by binding to and suppressing PGC1α transcriptional activity. In WAT, Id1 is mainly localized in the stromal vascular fraction, where the adipose progenitor/precursors reside. Lack of Id1 increases beige gene and Ucp1 expression in the WAT in response to cold exposure. Furthermore, brown-like differentiation is increased in Id1-deficient mouse embryonic fibroblasts. At the molecular level, Id1 directly interacts with and suppresses Ebf2 transcriptional activity, leading to reduced expression of Prdm16, which determines beige/brown adipocyte cell fate. Overall, the study highlights the existence of novel regulatory mechanisms between Id1/PGC1α and Id1/Ebf2 in controlling brown fat metabolism, which has significant implications in the treatment of obesity and its associated diseases, such as diabetes.

The cell polarity protein Scrib functions as a tumor suppressor in liver cancer.

Scrib is a membrane protein that is involved in the maintenance of apical-basal cell polarity of the epithelial tissues. However, Scrib has also been shown to be mislocalized to the cytoplasm in breast and prostate cancer. Here, for the first time, we report that Scrib not only translocates to the cytoplasm but also to the nucleus in hepatocellular carcinoma (HCC) cells, and in mouse and human liver tumor samples. We demonstrate that Scrib overexpression suppresses the growth of HCC cells in vitro, and Scrib deficiency enhances liver tumor growth in vivo. At the molecular level, we have identified the existence of a positive feed-back loop between Yap1 and c-Myc in HCC cells, which Scrib disrupts by simultaneously regulating the MAPK/ERK and Hippo signaling pathways. Overall, Scrib inhibits liver cancer cell proliferation by suppressing the expression of three oncogenes, Yap1, c-Myc and cyclin D1, thereby functioning as a tumor suppressor in liver cancer.

Contrasting effects of telomere shortening on organ homeostasis, tumor suppression, and survival during chronic liver damage.

Telomere shortening limits the regenerative capacity of cells during aging and chronic disease but at the same time inhibits tumor progression, and it has yet to be determined which of these mechanisms is dominantly affecting organismal survival. Here we show that telomere shortening in telomerase knockout (mTERC-/-) mice in combination with chronic liver damage significantly reduced organismal survival even though telomere shortening strongly inhibited liver tumor formation. Decreased survival induced by telomere shortening correlated with an imbalance between liver cell proliferation and liver cell apoptosis. Specific changes in gene expression were associated with telomere shortening and chronic liver damage and these gene expression changes were partially reversed by adenovirus mediated telomerase gene delivery. This study gives experimental evidence that the negative impact of telomere shortening on organ homeostasis and organismal survival can surpass the beneficial effects of telomere shortening on suppression of tumor growth in the setting of chronic organ damage.

Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis.

Telomere shortening limits the number of cell divisions of primary human cells and might affect the regenerative capacity of organ systems during aging and chronic disease. To test whether the telomere hypothesis applies to human cirrhosis, the telomere length was monitored in cirrhosis induced by a broad variety of different etiologies. Telomeres were significantly shorter in cirrhosis compared with noncirrhotic samples independent of the primary etiology and independent of the age of the patients. Quantitative fluorescence in situ hybridization showed that telomere shortening was restricted to hepatocytes whereas lymphocytes and stellate cells in areas of fibrosis had significantly longer telomere reserves. Hepatocyte-specific telomere shortening correlated with senescence-associated beta-galactosidase staining in 84% of the cirrhosis samples, specifically in hepatocytes, but not in stellate cells or lymphocytes. Hepatocyte telomere shortening and senescence correlated with progression of fibrosis in cirrhosis samples. This study demonstrates for the first time that cell type-specific telomere shortening and senescence are linked to progression of human cirrhosis. These findings give a novel explanation for the pathophysiology of cirrhosis, indicating that fibrotic scarring at the cirrhosis stage is a consequence of hepatocyte telomere shortening and senescence. The data imply that future therapies aiming to restore regenerative capacity during aging and chronic diseases will have to ensure efficient targeting of specific cell types within the affected organs.

Id transcriptional regulators in adipogenesis and adipose tissue metabolism.

Id proteins (Id1-Id4) are helix-loop-helix (HLH) transcriptional regulators that lack a basic DNA binding domain. They act as negative regulators of basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibit their DNA binding and transcriptional activity. Id proteins are implicated in the regulation of various cellular mechanisms such as cell proliferation, cellular differentiation, cell fate determination, angiogenesis and tumorigenesis. A handful of recent studies also disclosed that Id proteins have critical functions in adipocyte differentiation and adipose tissue metabolism. Here, we reviewed the progress made thus far in understanding the specific functions of Id proteins in adipose tissue differentiation and metabolism. In addition to reviewing the known mechanisms of action, we also discuss possible additional mechanisms in which Id proteins might participate in regulating adipogenic and metabolic pathways.

A dual role of Cdk2 in DNA damage response.

Once it was believed that Cdk2 was the master regulator of S phase entry. Gene knockout mouse studies of cell cycle regulators revealed that Cdk2 is dispensable for S phase initiation and progression whereby Cdk1 can compensate for the loss of Cdk2. Nevertheless, recent evidence indicates that Cdk2 is involved in cell cycle independent functions such as DNA damage repair. Whether these properties are unique to Cdk2 or also being compensated by other Cdks in the absence of Cdk2 is under extensive investigation. Here we review the emerging new role of Cdk2 in DNA damage repair and also discuss how the loss of Cdk2 impacts the G1/S phase DNA damage checkpoint.

p21 Inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint.

Cdk1 was proposed to compensate for the loss of Cdk2. Here we present evidence that this is possible due to premature translocation of Cdk1 from the cytoplasm to the nucleus in the absence of Cdk2. We also investigated the consequence of loss of Cdk2 on the maintenance of the G1/S DNA damage checkpoint. Cdk2(-/-) mouse embryonic fibroblasts in vitro as well as regenerating liver cells after partial hepatectomy (PH) in Cdk2(-/-) mice, arrest promptly at the G1/S checkpoint in response to gamma-irradiation due to activation of p53 and p21 inhibiting Cdk1. Furthermore re-entry into S phase after irradiation was delayed in Cdk2(-/-) cells due to prolonged and impaired DNA repair activity. In addition, Cdk2(-/-) mice were more sensitive to lethal irradiation compared to wild-type and displayed delayed resumption of DNA replication in regenerating liver cells. Our results suggest that the G1/S DNA damage checkpoint is intact in the absence of Cdk2, but Cdk2 is important for proper repair of the damaged DNA.

Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2.

It was believed that Cdk2-cyclin E complexes are essential to drive cells through the G1-S phase transition. However, it was discovered recently that the mitotic kinase Cdk1 (Cdc2a) compensates for the loss of Cdk2. In the present study, we tested whether Cdk2 can compensate for the loss of Cdk1. We generated a knockin mouse in which the Cdk2 cDNA was knocked into the Cdk1 locus (Cdk1Cdk2KI). Substitution of both copies of Cdk1 by Cdk2 led to early embryonic lethality, even though Cdk2 was expressed from the Cdk1 locus. In addition, we generated Cdk2-/- Cdk1+/Cdk2KI mice in which one copy of Cdk2 and one copy of Cdk1 were expressed from the Cdk1 locus and the Cdk2 gene was deleted from the endogenous Cdk2 locus. We found that both male and female Cdk2-/- Cdk1+/Cdk2KI mice were sterile, similar to Cdk2-/- mice, even though they expressed the Cdk2 protein from the Cdk1 locus in testes. The translocational and cell cycle properties of knockin Cdk2 in Cdk2-/- Cdk1+/Cdk2KI cells were comparable to those of endogenous Cdk2, but we detected premature transcriptional activation of Cdk1 during liver regeneration in the absence of Cdk2. This study provides evidence of the molecular differences between Cdk2 and Cdk1 and highlights that the timing of transcriptional activation and the genetic locus play important roles in determining the function of Cdk proteins in vivo.

The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo.

Telomere dysfunction induces two types of cellular response: cellular senescence and apoptosis. We analysed the extent to which the cellular level of telomere dysfunction and p53 gene status affect these cellular responses in mouse liver using the experimental system of TRF2 inhibition by a dominant-negative version of the protein (TRF2delta B delta M). We show that the level of telomere dysfunction correlates with the level of TRF2delta B delta M protein expression resulting in chromosomal fusions, aberrant mitotic figures and aneuploidy of liver cells. These alterations provoked p53-independent apoptosis, but a strictly p53-dependent senescence response in distinct populations of mouse liver cells depending on the cellular level of TRF2delta B delta M expression. Apoptosis was associated with higher expression of TRF2delta B delta M, whereas cellular senescence was associated with low levels of TRF2delta B delta M) expression. Our data provide experimental evidence that induction of senescence or apoptosis in vivo depends on the cellular level of telomere dysfunction and differentially on p53 gene function.

Telomeres and telomerase: a dual role in hepatocarcinogenesis.

Telomere shortening limits the proliferative capacity of primary human cells and restrains the regenerative capacity of organ systems during chronic diseases and aging. Telomere shortening apparently has a dual role in tumor development and progression. On the one hand, it induces chromosomal instability and the initiation of cancer; on the other hand, tumor progression requires stabilization of telomeres. The predominant mechanism of telomere stabilization in tumor cells is the activation of the telomere-synthesizing enzyme telomerase. The potential use of telomerase activators for the treatment of regenerative disorders will ultimately depend on their effects on tumorigenesis. This review focuses on the role of telomere shortening and telomerase in carcinogenesis with a special focus on hepatocellular carcinoma.