Expression Level And Oncological Significance Of FHL1 In Renal Cell Carcinoma, And Association Between MDM2, KLF6, AR Gene Polymorphisms And Urologic Neoplasms Susceptibility

LIM domain, possessing a highly conserved double zinc finger domain, is emerging as a hallmark of proteins that can associate with both actin cytoskeleton and transcriptional machinery. Four and a half LIM domain protein 1(FHL1) is one member of FHL LIM-only protein family, which consists of FHL1, FHL2, FHL3 and FHL5 in humans and presents four and a half LIM domains. Available researches about FHL1 are mainly focused on its association with myopathies, cardiovascular diseases and cancers. In renal cell carcinoma(RCC), research reports about FHL1 are very few. Only one research group examined its expression level by immunohistochemistry(IHC) in limited samples. By using q PCR, western blotting, IHC and plasmid transfection, we found out that FHL1 was significantly downregulated in RCC tissues in m RNA and protein level, FHL1 m RNA level had no relation with major clinical characteristics or survival rate of RCC, and FHL1 was upregulated by h MOF and involved in regulation of E-cadherin in RCC.Meanwhile, by using systematic review and meta-analysis, we estimated association between MDM2 SNP309 and skin cancers susceptibility, association between KLF6 IVS 1-27 G > A and prostate cancer susceptibility, and association between AR gene polymorphisms and TGCT susceptibility. MDM2 SNP309(rs2279744 T>G), whose frequency is much higher in SNPs in MDM2 gene’s promoter, increases binding affinity of Sp1, which results in high levels of MDM2 RNA and protein and subsequent changes in p53 pathway. KLF6 inter vening sequence(IVS) 1-27 G > A(rs3750861), a frequent SNP in intron 1 in position 3023(-27 upstream to exon 2) of KLF6 gene, abolishes the wild-type SF2/ASF and SRp55 binding sites, generates a functional SRp40 binding site and then increases alternative splicing(SV1, SV2, SV3, and IVS?A variant generated from IVS 1-27 G > A) but not decreases levels of wild-type KLF6. However, these increased KLF6 alternative splicing variants’ capacity for p21 up-regulation and cell proliferation decrease is weaker than the wild-type KLF6, which in turn antagonize wild-type KLF6’s capacity. CAG trinucleotide repeat region,(CAG)n CAA, is located in AR gene’s N-terminal transactivation domain(NTD) which encodes a polyglutamine(poly Q) tract in AR protein. Appropriate poly Q tract length is critical for maintenance of N/C interaction which can affect AR function. CAG repeat expansion in the region can also reduce AR m RNA and protein expression. GGN trinucleotide repeat region,(GGT)3GGG(GGT)2(GGC)n, is also located in AR gene’s NTD, however, the functional effect of GGN polymorphism remains unclear. Here we found out that MDM2 SNP309 may not be associated with the susceptibility of CM, however, there was insufficient data to fully confirm the association between MDM2 SNP309 and NMSC(BCC and SCC mainly). KLF6 IVS 1-27 G > A may not be associated with unselected prostate cancer susceptibility, however, there was insufficient data to fully confirm the association between KLF6 IVS 1-27 G > A and familial prostate cancer, sporadic prostate cancer. GGN repeat number<23 may not be associated with TGCT susceptibility, however, there was insufficient data to fully confirm association in GGN repeat number>23, CAG repeat number, SNP rs6152, rs1204038, rs2361634. Well?designed studies with larger sample size and more subgroups are required to validate the risk identified in the current meta?analysis.