Suppression of the TIG3 tumor suppressor gene in human ovarian carcinomas is mediated via mitogen‐activated kinase‐dependent and ‐independent mechanisms

Abstract

The TIG3 gene is a retinoic acid inducible class II tumor suppressor gene downregulated in several human tumors and malignant cell lines. Diminished TIG3 expression correlates with decreased differentiation whereas forced expression of TIG3 suppresses oncogenic signaling pathways and subsequently induces differentiation or apoptosis in tumor cells. Analysis of TIG3 mRNA expression in a large set of cDNA pools derived from matched tumor and normal human tissues showed a significant downregulation of TIG3 in 29% of the cDNA samples obtained from ovarian carcinomas. Using in situ hybridization, we demonstrated expression of TIG3 in the epithelial lining of 7 normal ovaries but loss of TIG3 expression in 15/19 of human ovarian carcinoma tissues. In SKOV-3, CAOV-3 and ES-2 ovarian carcinoma cell lines, downregulation of TIG3 mRNA was reversible and dependent on an activated MEK-ERK signaling pathway. Re-expression of TIG3 mRNA in these cells upon specific interference with the MEKpathway was correlated with growth inhibition of the cells. In OVCAR-3 and A27/80 ovarian carcinoma cells, TIG3 suppression is MEK-ERK independent, but expression could be reconstituted upon interferon gamma (IFNc) induction. Overexpression of TIG3 in A27/80 ovarian carcinoma cells significantly impaired cell growth and despite increased mRNA levels, TIG3 protein was hardly detectable. These results suggest that TIG3 is negatively regulated by an activated MEK-ERK signaling pathway. Further mechanisms must interfere with TIG3 expression that are independent of MEK and partially include interferon-responsive components. ' 2005 Wiley-Liss, Inc.

Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells

“…This indicates that the concerted loss of HRSL3 and RARRES3 from advanced ovarian carcinomas (Lotz et al, 2005;Sers et al, 2002) might allow a sustained activation of several distinct branches of the intracellular oncogenic signaling network.…”

“…HRSL3 was found to suppress growth of rodent and human carcinoma cells in vitro and in vivo and is downregulated in breast, ovary and kidney carcinomas (Husmann et al, 1998;Sers et al, 1997;Sers et al, 2002). The RARRES3 protein is suppressed in many human tumors such as ovarian (Lotz et al, 2005), gastric (Huang et al, 2000), colorectal (Huang et al, 2000;Shyu et al, 2003) and head and neck tumors (Higuchi et al, 2003), in psoriatic lesions and in basal cell carcinomas (Duvic et al, 2000;Duvic et al, 2003). It can activate type I transglutaminase by an unknown mechanism thereby inducing terminal differentiation (Sturniolo et al, 2003).…”

“…In cervical cancer cells, RARRES3 suppresses the activation of RAS proteins (Tsai et al, 2006) and negatively regulates the activity of Jun and p38 MAPKs (Huang et al, 2002). Interestingly, both HRASL3 and RARRES3 were identified as downstream targets of IFN␥ (Sers et al, 2002) and are suggested to regulate ovarian carcinoma cell growth by a concerted action (Lotz et al, 2005). However, whereas RARRES3 has been identified as a suppressor of RAS Journal of Cell Science 120 (8) Fig.…”

Regulation of Peroxisomal Lipid Metabolism by Catalytic Activity of Tumor Suppressor H-rev107

“…H-rev107 is the first member of this family to be discovered and has been characterized as a type II tumor suppressor (3)(4)(5). However, we recently found that this protein shows phospholipase A 1/2 (PLA 1/2 ) activity for glycerophospholipids with a preference for hydrolysis at the sn-1 position of the glycerol backbone (6,7).…”

RARRES3 (retinoic acid receptor responder (tazarotene induced) 3)

“…Prognosis Cancer prognosis is dependent upon several tumorspecific conditions, including location, size, and metastasis. Oncogenesis Loss of TIG3 mRNA and protein expression is observed in several cancers and may be necessary for oncogenesis (DiSepio et al, 1998;Casanova et al, 2001;Duvic et al, 2003;Shyu et al, 2003;Jiang et al, 2005;Lotz et al, 2005;Shyu et al, 2005). Tazarotene treatment of skin cancers leads to increased TIG3 expression and reduced proliferation (Duvic et al, 2000;Duvic et al, 2003).…”