Anosmin-1 involved in neuronal cell migration is hypoxia inducible and cancer regulated.
Functional expression of KAL1 gene is critical in the migration of GnRH neurons from the olfactory placode to the hypothalamus in embryogenesis. This gene thus far has not been shown to play a functional role in any other physiological or pathological process either in the developed brain or in peripheral tissues. We show here that KAL1 gene expression is decreased in early stage and increased in later stages of cancers. Screening of colon, lung and ovarian cancer cDNA panels indicated significant decrease in KAL1 expression in comparison to corresponding uninvolved tissues. However, KAL1 expression increased with the progression of cancer from early (I and II) stages to later (III and IV) stages of the cancer. There was a direct correlation between the TGFbeta and KAL1 expression in colon cancer cDNA. Using colon cancer cell lines, we showed that TGFbeta induces KAL1 gene expression and secretion of anosmin-1 protein (KAL1 coded protein). We further report that hypoxia induces anosmin-1 expression; anosmin-1 protects cancer cells from apoptosis activated by hypoxia and increases cancer cell mobility. Using siRNA technique we found that KAL1 expression following hypoxia is hypoxia-inducible factor (HIF-1)alpha dependent. Our results suggest that KAL1 gene expression plays an important role in cancer metastasis and protection from apoptosis.
Jian
Bixi
B
Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Nagineni
Chandrasekharam N
CN
Meleth
Sreelatha
S
Grizzle
William
W
Bland
Kirby
K
Chaudry
Irshad
I
Raju
Raghavan
R
D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003110:Colonic Neoplasms / Q000378:metabolism*; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D016212:Transforming Growth Factor beta / Q000378:metabolism
C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta