A cis‐eQTL genetic variant in PLK4 confers high risk of hepatocellular carcinoma

Abstract

PurposeThe overexpression and knockdown of PLK4 were both reported to generate aneuploidy. Thus, we aimed to investigate whether genetic variants in PLK4 contribute to the development of hepatocellular carcinoma (HCC).MethodsWe evaluated associations of common variants in PLK4 and its promoter for the risk of HCC in our association study (1300 cases and 1344 controls). The genotype‐tissue expression (GTEx) and The cancer genome atlas (TCGA) databases were used to quantify the expression of PLK4. Cell proliferation and migration affected by PLK4 in HCC were assessed in vitro. Drug susceptibility testing (DST) model was used to assess the sensibility of PLK4‐activated HCC to CFI‐400945, a small molecule inhibitor of PLK4.ResultsHerein, we found a significant association between rs3811741, located in the PLK4 intron, and liver cancer risk (OR = 1.26, P = 9.81 × 10−5). Although PLK4 expressed at lower levels in somatic tissues compared to the testis, the risk allele A of rs3811741 was associated with increased PLK4 expression in liver cancer tissues. Additionally, PLK4 high expression was remarkably associated with shortened survival of HCC (HR = 1.97, P = .001). Furthermore, overexpression of PLK4 promoted, while knockdown of PLK4 suppressed cancer cell proliferation, migration, and invasion. DST model demonstrated that CFI‐400945 can effectively suppress rampant proliferation of HCC with highly expressed PLK4.ConclusionTaken together, our study demonstrated that PLK4 is a susceptibility gene and plays an oncogenic role in HCC. Furthermore, we identified that PLK4 sensitives HCC to CFI‐400945, which may be an ideal therapy target for HCC.

Polo-Like Kinase 4’s Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy

“…Manson et al showed the selective antitumor activity of CFI-400945 in breast cancer cells in which Plk4 was overexpressed (158). Further investigations proved the remarkable antitumor effects of CFI-400945 in some kinds of cancers, including pancreatic cancer (166), lung cancer (207), liver cancer (140) and breast cancer (192). Interestingly, due to the self-regulating function of Plk4, CFI-400945 has a double effect on the number of centrioles by inhibiting Plk4: high concentration CFI-400945 inhibits the generation of centrioles, while low concentration CFI-400945 increases the number of centrioles possibly because partial Plk4 inhibition still phosphorylate downstream substrates (158).…”

“…These observations indicated that LOH, as well as epigenetic alternation of the Plk4 gene, reduces expression, which is critical to the development of HCC. However, other studies found that the upregulation of Plk4 was associated with poor prognosis in some HCC samples (73,140). Meng et al found that rs3811741, a functional cis-expression quantitative trait loci (eQTL) genetic variant of the Plk4 gene and located in the Plk4 intron, was significantly associated with HCC risk.…”

“…The high level Plk4 was related to risk allele A of rs3811741 in HCC tissues. The proliferation rate of HCC cells, in which the Plk4 levels were lower than in adjacent normal tissues, was significantly suppressed by a potent selective Plk4 inhibitor CFI-400945 (140,158). In addition, Bao et al showed that downregulation of miR-126 in HCC tissues increased the expression level of Plk4 via a ceRNA mechanism.…”

The cancer-testis gene, <i>MEIOB</i>, sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency

“…In addition, some studies show that cancers with genetic deficiencies involved in homologous recombination repair other than BRCA mutations, such as deficiencies in ATM, ATR, PALB2, and FANC, are also highly susceptible to PARP inhibitor treatment 10 , 11 . A group of cancer-testis (CT) genes is essential for homologous recombination 12 , 13 . These genes include the meiotic topoisomerase that catalyzes DNA double-strand breaks 14 , components of the synaptonemal complex (SYCP1) 15 , 16 , and multiple proteins that mediate homologue alignment or recombination (MEIOB) 17 , 18 .…”

Clinical significance of miR-1180-3p in hepatocellular carcinoma: a study based on bioinformatics analysis and RT-qPCR validation

“…Primary hepatic carcinoma is one of the most frequently occurring malignant tumors in the world. It is estimated that there are approximately 841,000 new cases and 782,000 deaths worldwide each year 1 , 2 . Hepatocellular carcinoma (HCC), the most common type of primary hepatic carcinoma, makes up 75% to 85% of all the liver cancers burden worldwide.…”