Search

Leucine-rich α2-glycoprotein (LRG) is an approximately 50-kDa glycoprotein that has been found to be elevated in the sera of patients with several types of cancer. LRG directly binds to transforming growth factor beta 1 (TGFβ1) and modulates TGFβ1 signaling in endothelial cells; however, the precise function of LRG in cancer remains unclear. This study aimed to investigate the role of LRG in cancer. Lewis lung carcinoma (LLC) cells hardly expressed LRG. The growth of LLC tumors allografted in the LRG knockout (KO) mice was significantly increased compared with wild-type (WT) mice. Conversely, overexpression of LRG significantly inhibited the growth of LLC tumors in WT mice. In the presence of LRG, TGFβ1 significantly inhibited the proliferation of LLC cells and human hepatocellular carcinoma Hep3B cells in vitro by inducing apoptosis via the potent activation of smad2 and its downstream signaling pathway. Furthermore, administration of a TGFβR1 inhibitor (SB431542) significantly enhanced the growth of LLC tumors in WT mice compared with LRG KO mice via inhibition of apoptosis. We propose that LRG potentiates the effect of TGFβ1 in cancer cells whose growth is suppressed in the presence of TGFβ1.

Background: Constitutive activation of STAT3 promotes oncogenesis and growth of oral squamous cell carcinoma (OSCC). We investigated the mechanism of action of suppressor of cytokine signaling 1 (SOCS1), an endogenous inhibitor of JAK, as gene therapy for OSCC. Methods: Antitumor effect of SOCS1 was compared to JAK inhibitor I by cell proliferation assay, cell cycle analysis, and apoptosis analysis in vitro. In addition, antitumor effect was evaluated using xenograft mouse models in vivo. Results: JAK inhibitor I inhibited the proliferation of KOSC2 cl3‐43 or T3M‐1 clone2 OSCC cell lines in vitro. While JAK inhibitor I arrested both cell lines at the G2/M phase, induction of apoptosis was observed in T3M‐1 clone2 cells, but not KOSC2‐cl3‐43 cells. An adenoviral vector expressing SOCS1 (AdSOCS1) significantly decreased the proliferation of both OSCC cell lines and induced G2/M phase cell cycle arrest and apoptosis, suggesting that induction of apoptosis of KOSC2 cl3‐43 cells by AdSOCS1 is regulated by the JAK/STAT independent pathway. Overexpression of SOCS1 inhibited activation of the JAK/STAT and p44/42 MAPK pathways, while JAK inhibitor I inhibited activation of the JAK/STAT pathway only. Consistently, expression of Mcl‐1 was decreased by overexpression of SOCS1, but not JAK inhibitor I. Additionally, KOSC2 cl3‐43 or T3M‐1 clone2 OSCC cells were subcutaneously implanted in the flanks of two xenograft mouse models. As compared to a control adenovirus vector (AdLacZ), intratumor injection of AdSOCS1 significantly decreased the tumor volume and induced apoptosis in vivo. Conclusion: SOCS1 gene therapy may be a beneficial approach for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Malignant melanoma is the most aggressive form of skin cancer, responsible for the majority of skin cancer-related deaths. Metastatic melanoma is resistant to surgery, radiation or chemotherapy, and an effective therapy has not yet been established. Our study investigated the therapeutic potential of the suppressor of cytokine signalling-1 (SOCS-1), an endogenous inhibitor of the intracellular cytokine signalling pathway, for treating melanoma. Adenovirus vectors encoding the SOCS-1 gene were used to overexpress SOCS-1 in three melanoma cell lines (G361, SK-MEL5 and SK-MEL28). In G361 and SK-MEL5, overexpression of SOCS-1 significantly reduced cell proliferation and induced apoptosis in vitro and in vivo. Furthermore, we indicated that the antiproliferative effect of SOCS-1 correlated not only with decreased levels of the activation of signal transducer and activator of transcription (STAT)3 but also with increased levels of p53 expression and phosphorylation. These findings indicate the potential for clinical use of SOCS-1 for melanoma treatment. [ABSTRACT FROM AUTHOR]