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By M.O.

The Ups and Downs of DNA Methylation in Gastric Tumors

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  2. The Ups and Downs of DNA Methylation in Gastric Tumors
  3. With HIV Drugs Against Cancer
  4. Synthetic siRNA Hampers Ewing Sarcoma

Yoshida et al., pp. 33–39

DNA methylation has important effects on gene expression, retrotransposition and carcinogenesis. Methylation usually occurs at CpG dinucleotides, which are often found in repetitive elements in the genome, known as Alu, LINE1 and Satα loci. Methylation of these sites serves to silence the genome-damaging activities of these elements while their demethylation is linked to lower genome stability, enhanced gene recombination, chromosome translocation and carcinogenesis.

Infection with Helicobacter pylori (HP) is a major cause of gastric cancer. Interestingly, aberrant DNA hypermethylation is induced as a consequence of HP infection. This methylation occurs mainly at “CpG islands” located in promoter regions of genes, which are generally hypomethylated to promote gene expression. To clarify the status of global DNA methylation in gastric cancers, Yoshida and colleagues examined samples of gastric mucosa collected by endoscopic biopsy from HP-negative or HP-positive volunteers. These volunteers were either healthy or afflicted with gastric cancer; in this case, only noncancerous tissue was examined.

The authors showed that Alu and Satα loci are hypomethylated in HP-infected gastric mucosa of healthy volunteers, and that Alu, but not Satα, hypomethylation persisted in patients with cancer. In contrast, LINE1 elements were only hypomethylated in patients with cancer. The authors speculate that hypomethylation of Alu and Satα elements may represent early events of gastric carcinogenesis induced by HP infection whereas LINE1 hypomethylation may occur as a consequence of cellular transformation processes.

By M.O.

With HIV Drugs Against Cancer

  1. Top of page
  2. The Ups and Downs of DNA Methylation in Gastric Tumors
  3. With HIV Drugs Against Cancer
  4. Synthetic siRNA Hampers Ewing Sarcoma

Toschi et al.

Drugs that inhibit the viral protease are critical components of the therapeutic regimen of individuals carrying the HIV virus. While the introduction of these protease inhibitors has dramatically prolonged the life expectancy of HIV-infected patients, the need for lifelong intake has generated concerns about side effects. Indeed, several unwanted symptoms have been observed in those taking the therapy, such as diabetes, lipodystrophy and liver damage.

…both inhibitors reduced tumor microvascular densities…and invasion of tumor cells in vivo

Here, Toschi and colleagues study a surprising, positive side effect of the drugs: a decrease in HIV-associated cancers. A reduction in the incidence of Kaposi sarcomas, non-Hodgkin lymphomas and cervical cancer has been observed in HIV-infected patients and has been attributed to the improved immune status after therapy. However, the reduction is also observed when therapy fails and immune functions do not improve.

The authors performed experiments in nude mice in the absence of HIV infection and show that two HIV protease inhibitors, indinavir and saquinavir, inhibit the growth of common tumors, such as colon, breast, lung and liver carcinomas. Only saquinavir in unphysiologically high doses inhibited the activity of the cell proteasomes, cellular complexes that break down proteins and that have been implicated in the drugs' activities before. Instead, both inhibitors reduced tumor microvascular densities (40–65%) and invasion of tumor cells in vivo, a process linked to the reduced activities of matrix metalloproteinases-2 and -9. The authors propose that protease inhibitors in combination with cytotoxic drugs may be promising new therapeutics that may also help cancer patients not afflicted with HIV infection.

By Anne Forde

Synthetic siRNA Hampers Ewing Sarcoma

  1. Top of page
  2. The Ups and Downs of DNA Methylation in Gastric Tumors
  3. With HIV Drugs Against Cancer
  4. Synthetic siRNA Hampers Ewing Sarcoma

Takigami et al., pp. 216–226

DOI : 10.1002/ijc.25564

Ewing sarcoma is the second most common malignant bone tumor that mainly affects children and young adults. Of the Ewing sarcomas, 85% display a fusion gene – EWS/Fli-1 – which is a product of chromosomal translocation. The EWS fusion gene is thought to play a significant role in tumorigenesis and it has been reported that tumorigenesis of Ewing sarcoma cell lines can be reduced by antagonizing the gene.

In this study, Takigami et al., created a chemically synthesized siRNA system to block EWS fusion protein. Two siRNA were generated: both targeted a specific form of EWS fusion gene, but one also possessed the aromatic compound pyridine at the 3′ end. The siRNAs reduced EWS fusion protein in Ewing sarcoma cell lines that expressed that specific form of gene product. siRNA-induced knockdown of EWS fusion protein correlated with decreased proliferation of the sarcoma cell lines but did not affect the viability of the cells as monitored by apoptosis.

In vivo, tumor growth was significantly suppressed in Ewing sarcoma tumor-bearing mice injected with the siRNAs. Importantly, the animals did not show any adverse effects of the siRNA treatment. The siRNA that included the aromatic compound performed more stably in vivo.

This study nicely demonstrates that synthetic siRNAs specific for EWS fusion can reduce expression of the protein and can inhibit the growth of Ewing sarcoma tumors in vivo. The siRNA version with an aromatic compound, in particular, offered stability without adverse side effects.

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Illustration 1. Inhibition of Ewing Sarcoma tumors in BALB/c nude mice with synthetic siRNAs targeting the EWS fusion gene: siEFp (siRNA with an aromatic compound pyridine at the 3′ end), siEF (not modified at 3′ end), siCONT (control siRNA) and PBS. The frequency at which the siRNAs were given to the animals is indicated by arrows.

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