Examples of the fragile telomeres in TRF1-deleted MEF metaphases. • Telomeric DNA, FITC PNA probe (green); DNA, DAPI (blue). Cell, 2009 Telomere shortening : Failed Telomeric DNA replication • Fragile sites are prone to sister chromatid exchanges, often undergo rearrangements, and are frequent targets of integration of exogenous DNA, And replication-fork stalling is observed in the fragile sites. • Mammalian telomeres resemble fragile sites. • TRF1 acts by recruiting/activating these helicases to telomeres, • so might repress replication problems.

Telomere Dysfunction-Induced Focus : Gross DNA damage가 아닌 telomere 특이적인 damage임을 확인하는 방법, T-FISH와 동시에 DNA damage marker를 타겟으로 하는 immunostaining을 함께 적용. mitochondrial Superoxide production PLoS Bioology, 2007 Telomere shortening : Telomeric damage (e.i. caused by free radical..) • High mitochondrial superoxide production show the same frequency of TIFs

Gene & Dev. , 2005 Telomere shortening : Unprotected telomeric structure • Shelterin: A complex formed by six telomere-specific proteins associates with this sequence and protects chromosome ends. • Shleterin allows cells to distinguish telomeres from sites of DNA damage.

Correlation of telomere length and Hepatocellular senescence with fibrosis progression. Stefanie et al., 2002 • Samples with severe fibrosis have significantly shorter telomeres and higher rates of hepatocyte senescence than samples with milder fibrosis. • Continuous liver damage and concominant regeneration accelerate telomere shortening. These defects lead to senescence and cessation of regeneration. And continuous liver damage at this point triggers the fibrotic scarring.

Hepatocellular carcinoma (HCC) 과정에 따른 telomere 양상: 환자 샘플을 이용한 연구 Plentze et al., 2006 DN Telomere Shortening During Multistep Hepatocarcinogenesis. HCC (Grade 별로 나누지 않음)

Dedifferentiated HCCs showed telomere lengthening. Telomere length were longer in HCCs with poorer differentiation (P=0.041; 7.7±1.80 kb in grade I and II HCCs vs 8.7±1.66 kb in grade III and IV HCCs). 44.4% of HCCs showed telomere lengthening. Oh et al., 2008 Oh et al., 2008 • Long telomeres are poor prognostic markers for HBV-related HCCs.

TR Bessler et al., (2007) Telomerase • The ribonucleoprotein enzyme telomerase is a specialized reverse transcriptase that synthesizes telomeric DNA by copying a template sequence within the telomerase RNA (E.H. Blackburn et al., 1996).

hTERT mRNA levels During Human Multi-Step Hepatocarcinogenesis normal livers, chronic hepatitis (CH), liver cirrhosis (LC), large regenerative nodules (LRNs), low-grade dysplastic nodules (LGDNs), high-grade dysplastic nodules (HGDNs), DNs with hepatocellular carcinoma(HCC) foci HCCs. Oh et al., 2006 • The hTERT mRNA levels increased with the progression of hepatocarcinogenesis, and a significant induction in the transition between low- and high-grade DNs was seen.

Telomerase activity During Human Multi-Step Hepatocarcinogenesis Park et al., 1998 • Telomerase is strongly activated in hepatocellular carcinoma • but not in chronic hepatitis and cirrhosis

Telomere shortening in HBV-related Cirrhosis than in cholestasis-related Cirrhosis Normal- looking hepatocytes Normal- looking hepatocytes cirrhosis cirrhosis Kim et al., 2009 • When LLCC in HBV-related cirrhosis was compared with those in chronic cholestasis, HBV-related LLCC showed significantly telomere shortening.

Hepatology., 2009

The significance of LLCC as a precursor to HCC is still controversial. But LLCC that was associated with chronic HBV infection demonstrated molecular characteristics different from that in chronic cholestasis (Hepatology, 2009). Cholestasis is a condition where bile cannot flow from the liver to the duodenum. Because bile acid are highly toxic, a defect in bile acid transport induce severe liver disease (The Liver, LIPPINCOTT WILLIAMS & WILKINS). Cholestasis HBV-infectec • LLCC (Large Liver cell change) arising in cholestatic livers may represent reactive change • With a more stringent cell cycle checkpont control. (Hepatology, 2009).

Hepatocellular carcinoma (HCC) 과정에 따른 telomere 양상: Cell study Jiun-Ming Su et al., 2007 • HBx can induce telomere shortening by acting as a transcriptional corepressor of MAZ on the human telomerase promoter.

Hepatocellular carcinoma (HCC) 과정에 따른 telomere 양상: Cell study pCMV-HBX vector OPTIMEM medium empty vector Sheng-Quan Zou et al., 2004 • HBx can up-regulate hTERT mRNA expression in normal human cholangiocytes.

Rob, End-to end Chromosomal fusion; T, Translocation Rudolph KL et al., 1999 Artandi et al., 2000 Telomerase-deficient mice • Telomere attrition in telomerase-deficient mice promotes the cancers by chromosomal instability that includes theformation of end-to-end fusion and translocation

4.32 % 18.0 % 13.7 % Artandi et al., 2000 Telomerase-deficient mice • Telomere shortening in ageing mTERC-/- mice is associated with increased rates of cancer.

6 months after repeated CCl4-induced liver injury. steatosis fibrosis Science, 2000 Hepatocellular carcinoma (HCC) 과정에 따른 telomere 양상: Animal model • Telomere dysfunction was associated with defects in liver regeneration and accelerated the development of liver cirrhosis in response to chronic liver injury. • Telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement.

Telomere during carcinogenesis Cirrhosis---G1-G2(?) HCC------------ Normal Genetic Change (=Genome Alteration =Chromosomal Aberrant =Chromosome Instability =Highly rearranged Genomes) Tumorigenesis & Metastasis Telomere Length Telomere Lengthening  Cancer Progression Telomere Function Intact Telomere Dysfunction Telomere Shortening  Cell Death

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