Candidate target genes of hsa-miR-424-5p and hsa-miR-377 Gene name Main pathway Target Accession gene ID hsa-miR-424-5p Hypoxia and angiogenesis HIF1A MIRT005926 CUL2
MIRT005927 Cell cycle CDK6 MIRT000938 CCND1 MIRT000941 CCNE1 MIRT000936 CCND3 MIRT000937 hsa-miR-377 MAPK pathway PPM1A MIRT000990 PI3K-akt pathway PAK1 MIRT000991 HIF1A: Hypoxia-inducible factor 1A; CUL2
: Cullin 2; CDK: Cyclin-dependent kinase; CCND1: Cyclin D1; CCNE1: Cyclin E1; CCND3: Cyclin D3; MAPK: Mitogen-activated protein kinase; PPM1A: Protein phosphatase magnesium-dependent 1A; PI3K: Phosphatidyl inositol 3'-kinase; PAK1: p21-activated kinase 1.
pVHL forms a complex with Elongin BC, Cul2
, and Rbx1 , and this complex, which acts as a ubiquitin ligase, polyubiquitinates HIF-1[alpha], leading to its degradation in the 26S proteasome [16, 17].
VHL is a component of the VHL elongin BC complex--composed of the proteins VHL, CUL2 or CUL5, RBX1, and elongin B/elongin C (elongins B and C are encoded by TCEB1 and TCEB2, resp.).
Information regarding DNA copy number alterations affecting VHL tumor suppressor complex components (VHL, TCEB1, TCEB2, RBX1, CUL2, and CUL5) was obtained from 171 PCC tumors available through The Cancer Genome Atlas Project (TCGA).
VHL complex component genes (CUL2, CUL5, TCEB1, TCEB2, and RBX1) as well as 3 genes known to be frequently mutated in PCC (RET, HRAS, and NF1) were classified as having an inactivating mutation if the result was a frame shift insertion, frame shift deletion, splice site mutation, missense mutation, or a nonsense mutation.
CUL2 did not exhibit any gene CNL according to our parameters.
TCEB2, which had a gene CNL frequency of 2.9%, was not significantly correlated with expression; CUL2 was not altered at the copy number level.
miR-424 promotes angiogenesis by inhibiting cullin 2 (CUL2
), thereby increasing HIF-la levels .
pombe); CHUK, conserved helix-loop-helix ubiquitous kinase; CREBBP, CREB binding protein (also known as CBP); CUL2
, cullin 2; DAPK1, death-associated protein kinase 1; DAPK2, death-associated protein kinase 2; DAPK3, death-associated protein kinase 3; DGCR8, DiGeorge syndrome critical region gene 8; DROSHA, drosha, ribonuclease type III; E2F1, E2F transcription factor 1; EGF, epidermal growth factor; EGFL7, EGF-like-domain, multiple 7; EGFR, epidermal growth factor receptor; EGLN1, egl nine homolog 1 (C.
The order of thermal stabilities these compounds were found: CuL4 > CuL1 > CuL6 > CuL2
, 5 > CuL3 > L5 > L1, 2, 4> L3 > L6, which may be attributed to the specific chemical structures of the synthesized ligands and copper(II) complexes.