Role of a Novel Lysophospholipase in Tumorigenesis

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DESCRIPTION (provided by applicant): Phospholipids and lysophospholipids are known to act as lipid mitogens that regulate cell proliferation and survival signaling pathways. The levels of these lipids are tightly regulated by their respective lipases and thus, the expression and activity of these enzymes is critical for cellular homeostasis. We have cloned a cDNA that encodes a novel putative lysophospholipase. In view of its predicted molecular mass of 34 kDa, we have named it LPL34 (Lysophospholipase 34). Preliminary results suggest that LPL34 contains lipase activity. Our preliminary results also show that LPL34 mRNA is highly expressed in normal colon mucosa but absent or reduced in established colon cancer cell lines. LPL34 mRNA expression is also lost or reduced in 63% (24/38) of primary colon cancers when compared to their matching normal tissues. Using purified LPL34 protein, we have generated two high quality LPL34 antibodies. Western blot and immunohistochemistry analyses using these antibodies demonstrate that LPL34 protein expression is also significantly reduced in all primary colon tumors tested. Consistent with these results, expression of exogenous LPL34 in cancer cells lacking endogenous LPL34 results in growth inhibition suggesting that LPL34 appears to be a novel tumor suppressor. To investigate the relevance of LPL34 alterations in colon tumoriogenesis, we will examine LPL34 protein expression status in matching primary colon normal and tumor specimens and correlate LPL34 expression with various clinicapathological parameters. The molecular mechanism(s) responsible for LPL34 down-regulation in colon tumor will be investigated and the role of lipase activity of LPL34 in cellular growth suppression will also be determined. To further understand the physiological function(s) of LPL34 in cell growth control, we will initiate studies to identify and study its potential lipid substrates and interacting proteins. To delineate the role of LPL34 in the GI malignancies, we propose to generate inducible conditional deletion of LPL34 in the GI tract of transgenic mice. The outcome of these studies will provide important information about (1) the value of LPL34 as diagnostic/prognostic marker, (2) the molecular mechanism(s) of action of this novel lysophospholipase in normal cell growth and (3) its contribution in colon cancer development. PUBLIC HEALTH RELEVANCE: Phospholipids and lysophospholipids are known to act as lipid mitogens that regulate cell proliferation and survival signaling pathways. The levels of these lipids are tightly regulated by their respective lipases and thus, the expression and activity of these enzymes is critical for cellular homeostasis. We have cloned a cDNA that encodes a novel putative lysophospohlipase, named LPL34. Our preliminary results suggest that LPL34 contains lipase activity and may be involved in colon cancer development. We have proposed three specific aims to study this novel lysophospholipase. The outcome of these studies will provide important information about (1) the value of LPL34 as diagnostic/prognostic marker, (2) the molecular mechanism(s) of action of this novel lysophospholipase in normal cell growth and (3) its contribution in colon cancer development.