Essential role of sphingosine-1-phosphate receptor 1-bearing CD8+CD44+CCR7+ T cells in acute skin allograft rejection.

A subset of naturally formed sphingosine-1-phosphate receptor 1 (S1P1)-bearing CD8(+)CD44(+)CCR7(+) memory T cells has been identified in transplant recipient BALB/c (H-2(d)) mice. The frequency of this subset of memory T cells is significantly increased in the spleen, lymph nodes and skin grafts in the recipient BALB/c mice during acute skin allograft rejections. The immune-reconstitution with CD8(+)CD44(+)CCR7(+)S1P1(+) memory T cells facilitates acute skin allograft rejection in SCID mice. Being Th1-polarized and cytotoxic, CD8(+)CD44(+)CCR7(+)S1P1(+) memory T cells proliferate and differentiate immediately into effectors upon encountering allo-antigens. A siRNA against S1P1 inhibits CD8(+)CD44(+)CCR7(+)S1P1(+) memory T cell-mediated acute skin allograft rejection in SCID mice by means of knocking-down S1P1-expression. CCL21 mutant (CCL21-DeltaCT) has been used to compete with wild-type CCL21 in the course of binding to CCR7. Combined administration of siRNA S1P1 and CCL21-DeltaCT significantly prolongs the survival of skin allograft in the recipient BALB/c mice by means of inhibiting accumulation of CD8(+)CD44(+)CCR7(+)S1P1(+) memory T cells in the spleen and the skin grafts. Our data provide direct evidence that S1P1 and CCR7 are involved in the proliferation and trafficking of CD8(+)CD44(+)CCR7(+)S1P1(+) memory T cells. S1P1 may serve as a functional marker for CD8(+)CD44(+)CCR7(+) memory T cells. Targeting CD8(+)CD44(+)CCR7(+)S1P1(+) T cells may be a useful strategy to prolong the survival of allograft transplant.

Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells.

The molecular mechanism of striking higher prevalence of hepatocellular carcinoma (HCC) in male subjects has not yet been fully elucidated. Here, we report that androgen receptor (AR) is differentially expressed in different HCC cell lines. AR agonist dihydrotestosterone (DHT) enhances HCC cell growth and apoptotic resistance. Antagonist flutamide (FLU) blocks the effects of DHT on the HCC cell lines. Paternally expressed gene 10 (PEG10) is expressed in HCC cell lines at substantial high level. Using small interfering RNAs against AR and PEG10 in AR- and PEG10-expressing BEL-7404 hepatoma cells and HuH7 hepatoma cells (HuH7) cells, and AR-transfection technique in AR-lacking and PEG10-expressing HepG2 cells, we have confirmed that through upregulation and activation of PEG10, DHT enhances HCC cell growth and apoptotic resistance. We have further demonstrated that DHT upregulates expression of human telomerase reverse transcriptase (hTERT) in HCC cell lines in a PEG10-dependent manner. Moreover, AR directly interacts in vivo with androgen-responsive elements in the regions of promoter and exon 2 of PEG10 gene in HCC cell lines. DHT promotes the hepatoma formation in vivo nude mice through PEG10 activation. AR antagonists (FLU and valproate) inhibit the hepatoma formation. These findings suggest that PEG10 plays an essential role in hepatocarcinogenesis. The PEG10 inhibition can be a novel approach for therapy of HCC.