Downregulated LRRK2 gene expression inhibits proliferation and migration while promoting the apoptosis of thyroid cancer cells by inhibiting activation of the JNK signaling pathway

Abstract

Emerging studies have indicated that leucine-rich repeat kinase 2 (LRRK2) is associated with thyroid cancer (TC). The present study investigated the effect of LRRK2 on the cell cycle and apoptosis in TC, and examined the underlying mechanisms in vitro . To screen TC-associated differentially expressed genes, gene expression microarray analysis was conducted. Retrieval of pathways associated with TC from the Kyoto Encyclopedia of Genes and Genomes database indicated that the c-Jun N-terminal kinase (JNK) signaling pathway serves an essential role in TC. SW579, IHH-4, TFC-133, TPC-1 and Nthy-ori3-1 cell lines were used to screen cell lines with the highest and lowest LRRK2 expression for subsequent experiments. The two selected cell lines were transfected with pcDNA-LRRK2, or small interfering RNA against LRRK2 or SP600125 (a JNK inhibitor). Subsequently, flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, a 5-ethynyl-2′-deoxyuridine assay and a scratch test was conducted to detect the cell cycle distribution, apoptosis, proliferation and migration, respectively, in each group. The LRRK2 gene was determined to be elevated in TC based on the microarray data of the GSE3678 dataset. The SW579 cell line was identified to exhibit the highest LRRK2 expression, while IHH-4 cells exhibited the lowest LRRK2 expression. LRRK2 silencing, through inhibiting the activation of the JNK signaling pathway, increased the expression levels of genes and proteins associated with cell cycle arrest and apoptosis in TC cells, promoted cell cycle arrest and apoptosis, and inhibited cell migration and proliferation in TC cells, indicating that LRRK2 repression could exert beneficial effects through the JNK signaling pathway on TC cells. These observations demonstrate that LRRK2 silencing promotes TC cell growth inhibition, and facilitates apoptosis and cell cycle arrest. The JNK signaling pathway may serve a crucial role in mediating the anti-carcinogenic activities of downregulated LRRK2 in TC.

Identification of hub driving genes and regulators of lung adenocarcinoma based on the gene Co-expression network

“…Moreover, they also confirmed that the down-regulation of LRRK2 in cultured tumor cells compromises MET activation and selectively reduces downstream MET signaling to mTOR and STAT3. Similarly, LRRK2 also showed anti-carcinogenic activities in the study by Jiang et al [37], which coincided with our analysis in LUAD. With the further exploration of LRRK2, it is noteworthy that LRRK2 CNV alteration showed high incidence and LRRK2 was correlated with various immune cells' infiltration levels, which provided multiple levels of evidence for the importance of LRRK2 in LUAD and also made LRRK2 more reliable as an independent prognostic signature.…”

LRRK2 inhibition potentiates PARP inhibitor cytotoxicity through inhibiting homologous recombination‐mediated DNA double strand break repair

“…Emerging evidence suggests that LRRK2 mutations are highly related with cancers such as colon cancer and nonskin cancer 10,11 . Article also reported that LRRK2 is overexpressed in thyroid cancer 12 . Here, we noticed that in OC patients, LRRK2 high expression is associated with advanced clinical factors.…”

“…10,11 Article also reported that LRRK2 is overexpressed in thyroid cancer. 12 Here, we noticed that in OC patients, LRRK2 high expression is associated with advanced clinical factors. All the findings indicate that OCs expressing high levels of LRRK2 are more resistant to treatment potentially through promoting the HR pathway.…”

SNPs within microRNA binding sites and the prognosis of breast cancer

“…Lin et al identified a LINK-A lncRNA that mediated HIF1α phosphorylation at Ser797 by LRRK2, resulting in the activation of normoxic HIF1α signaling and promoting glycolysis reprogramming, tumorigenesis and progression in triple-negative breast cancer [ 33 ]. Jiang et al revealed that downregulated LRRK2 gene expression inhibited proliferation and migration while promoting the apoptosis of thyroid cancer cells by inhibiting activation of the JNK signaling pathway [ 34 ].…”