Evidence for horizontal gene transfer between Chlamydophila pneumoniae and Chlamydia phage.

Chlamydia-infecting bacteriophages, members of the Microviridae family, specifically the Gokushovirinae subfamily, are small (4.5-5 kb) single-stranded circles with 8-10 open-reading frames similar to E. coli phage ϕX174. Using sequence information found in GenBank, we examined related genes in Chlamydophila pneumoniae and Chlamydia-infecting bacteriophages. The 5 completely sequenced C. pneumoniae strains contain a gene orthologous to a phage gene annotated as the putative replication initiation protein (PRIP, also called VP4), which is not found in any other members of the Chlamydiaceae family sequenced to date. The C. pneumoniae strain infecting koalas, LPCoLN, in addition contains another region orthologous to phage sequences derived from the minor capsid protein gene, VP3. Phylogenetically, the phage PRIP sequences are more diverse than the bacterial PRIP sequences; nevertheless, the bacterial sequences and the phage sequences each cluster together in their own clade. Finally, we found evidence for another Microviridae phage-related gene, the major capsid protein gene, VP1 in a number of other bacterial species and 2 eukaryotes, the woodland strawberry and a nematode. Thus, we find considerable evidence for DNA sequences related to genes found in bacteriophages of the Microviridae family not only in a variety of prokaryotic but also eukaryotic species.

Chemokine receptor CXCR4-mediated transformation of mammary epithelial cells by enhancing multiple RTKs expression and deregulation of the p53/MDM2 axis.

Recent studies have shown that CXCR4 is associated with tumor metastasis. Elevated levels of CXCR4 are also detected in a high percentage of DCIS cases. The high frequency of CXCR4 expression in DCIS suggests that many DCIS cases are "primed" for invasiveness. In this study, we demonstrated that expression of CXCR4 reveals morphological alterations in cells, from normal acinar morphological epithelial cells to a more invasive morphology in a 3D-culture system. Ectopic expression of CXCR4 induces invasion of MCF-10A cells. Interestingly, CXCR4 is capable of orchestrating a complex alteration in signaling networks, which include upregulation of multiple receptor tyrosine kinases (RTKs), deregulation of p53/MDM2 axis, upregulation of E-cadherin and c-myc, as well as modulation of cell cycle molecules to facilitate mammary epithelia cell transformation. These findings reveal that CXCR4 expression exerts a critical role in early stages of breast lesions, which may explain the high frequency of CXCR4 expression detected in DCIS. We believe that these studies will lead to new, biologically-based therapeutic strategies for clinical intervention, prevention and treatments of breast cancer.

CXCR4 suppression attenuates EGFRvIII-mediated invasion and induces p38 MAPK-dependent protein trafficking and degradation of EGFRvIII in breast cancer cells.

Our previous report has shown that the constitutively activated EGFR variant, EGFRvIII, up-regulates the pro-metastatic chemokine receptor CXCR4 in breast cancer cells. Here we evaluated the biological effect and cell signaling effects of silencing CXCR4 expression in EGFRvIII-expressing breast cancer cells. Short hairpin RNA (shRNA)-mediated suppression of CXCR4 expression significantly reduced the invasive potential and proliferation of EGFRvIII-expressing breast cancer cells. These cells exhibited a reduction of EGFRvIII activity and protein expression due to increased protein degradation and altered protein trafficking. In conclusion, suppression of CXCR4 inhibits EGFRvIII-mediated breast cancer cell invasion and proliferation.