KIAA1217 Promotes Epithelial-Mesenchymal Transition and Hepatocellular Carcinoma Metastasis by Interacting with and Activating STAT3.

The survival and prognosis of hepatocellular carcinoma (HCC) are poor, mainly due to metastasis. Therefore, insights into the molecular mechanisms underlying HCC invasion and metastasis are urgently needed to develop a more effective antimetastatic therapy. Here, we report that KIAA1217, a functionally unknown macromolecular protein, plays a crucial role in HCC metastasis. KIAA1217 expression was frequently upregulated in HCC cell lines and tissues, and high KIAA1217 expression was closely associated with shorter survival of patients with HCC. Overexpression and knockdown experiments revealed that KIAA1217 significantly promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) in vitro. Consistently, HCC cells overexpressing KIAA1217 exhibited markedly enhanced lung metastasis in vivo. Mechanistically, KIAA1217 enhanced EMT and accordingly promoted HCC metastasis by interacting with and activating JAK1/2 and STAT3. Interestingly, KIAA1217-activated p-STAT3 was retained in the cytoplasm instead of translocating into the nucleus, where p-STAT3 subsequently activated the Notch and Wnt/ß-catenin pathways to facilitate EMT induction and HCC metastasis. Collectively, KIAA1217 may function as an adaptor protein or scaffold protein in the cytoplasm and coordinate multiple pathways to promote EMT-induced HCC metastasis, indicating its potential as a therapeutic target for curbing HCC metastasis.

KIAA1217: A novel candidate gene associated with isolated and syndromic vertebral malformations.

Vertebral malformations (VMs) are caused by alterations in somitogenesis and may occur in association with other congenital anomalies. The genetic etiology of most VMs remains unknown and their identification may facilitate the development of novel therapeutic and prevention strategies. Exome sequencing was performed on both the discovery cohort of nine unrelated probands from the USA with VMs and the replication cohort from China (Deciphering Disorders Involving Scoliosis & COmorbidities study). The discovery cohort was analyzed using the PhenoDB analysis tool. Heterozygous and homozygous, rare and functional variants were selected and evaluated for their ClinVar, HGMD, OMIM, GWAS, mouse model phenotypes, and other annotations to identify the best candidates. Genes with candidate variants in three or more probands were selected. The replication cohort was analyzed by another in-house developed pipeline. We identified rare heterozygous variants in KIAA1217 in four out of nine probands in the discovery cohort and in five out of 35 probands in the replication cohort. Collectively, we identified 11 KIAA1217 rare variants in 10 probands, three of which have not been described in gnomAD and one of which is a nonsense variant. We propose that genetic variations of KIAA1217 may contribute to the etiology of VMs.

Genetic polymorphism of KIAA1217 is functionally associated with lumbar disc herniation in the Chinese population.

BACKGROUND: Genetic polymorphism of KIAA1217 has been reported to be associated with lumbar disc herniation (LDH) in different populations such as Japanese population and Finnish population. This study aimed to explore whether the genetic polymorphism of KIAA1217 is functionally associated with LDH in Chinese population. METHODS: SNP rs16924573 of KIAA1217 was genotyped in 1272 patients and 1248 healthy controls. The mRNA expression of KIAA1217 in the intervertebral disc was analyzed for 84 patients and 32 controls. The differences of genotype and allele distributions between LDH patients and healthy controls were evaluated using the Chi-square test. One-way ANOVA test was used to compare the relationship between genotypes and tissue expression of KIAA1217. RESULTS: Patients were found to have significantly higher frequency of genotype GG of rs16924573 than the controls (64.2% vs. 52.8%, p<0.001). The frequency of allele G was remarkably higher in the patients than in the controls (79.8% vs. 73.2%, p<0.001), with an OR of 1.45 (95% confidential interval=1.27-1.66). Compared with the controls, LDH patients were observed to have significantly decreased expression of KIAA1217. Patients with genotype GG had remarkably lower mRNA expression of KIAA1217 than those with genotype AG or AA (p=0.01). CONCLUSIONS: SNP rs16924573 of KIAA1217 could be functionally associated with LDH in the Chinese population. More in vivo and vitro experiments need to be carried out to further clarify the regulatory mechanism of functional variants in KIAA1217.

Effects of nonsynonymous single nucleotide polymorphisms of the KIAA1217, SNTA1 and LTBP1 genes on the growth traits of Ujumqin sheep.

Sheep body size can directly reflect the growth rates and fattening rates of sheep and is also an important index for measuring the growth performance of meat sheep. In this study, high-resolution resequencing data from four sheep breeds (Dorper sheep, Suffolk sheep, Ouessant sheep, and Shetland sheep) were analyzed. The nonsynonymous single nucleotide polymorphisms of three candidate genes (KIAA1217, SNTA1, and LTBP1) were also genotyped in 642 healthy Ujumqin sheep using MALDI-TOFMS and the genotyping results were associated with growth traits. The results showed that different genotypes of the KIAA1217 g.24429511T>C locus had significant effects on the chest circumferences of Ujumqin sheep. The SNTA1 g.62222626C>A locus had different effects on the chest depths, shoulder widths and rump widths of Ujumqin sheep. This study showed that these two sites can be used for marker-assisted selection, which will be beneficial for future precision molecular breeding.

Bronchial salivary gland-type intraductal carcinoma with KIAA1217::RET gene fusion composed of intercalated and oncocytic components.

Salivary gland-type intraductal carcinoma (IC) is a rare malignant salivary gland neoplasm. Primary salivary gland-type IC has never been described in the lung. Herein, we present a primary pulmonary IC in a 63-year-old woman. The tumor originated in the bronchus wall of the right middle lobe. The tumor consisted of two histological types, intercalated component and oncocytic component. The intercalated component showed tubular/cystic pattern composed of column to cube-shaped cells and scattered mucous cells. The oncocytic component showed solid nests composed of large cells with abundant eosinophilic granular cytoplasm. Immunohistochemically, both histological components were positive for cytokeratin 7 (CK7), S-100 protein, SOX10, and mammaglobin. The rimming myoepithelial cells were highlighted by p63 and smooth muscle actin (SMA). The tumor cells were negative for androgen receptor (AR), HER-2, Dog-1, TTF-1, napsin A, GCDFP-15, and GATA3. In the present case, we detected KIAA1217::RET fusion via DNA-based next-generation sequencing (NGS) and RT-PCR, which established the diagnosis of IC at a molecular level. The present case expands the categories of bronchopulmonary salivary gland-type tumors.

Identification of a novel FGFR2-KIAA1217 fusion in esophageal gastrointestinal stromal tumours: A case report.

Background: Gastrointestinal stromal tumours (GISTs) rarely arise in the esophagus. The clinical course and treatment options for esophageal GISTs are poorly understood because of their rarity. In general, the mutation spectrum of esophageal GISTs resembles that of gastric GISTs. Wild-type (WT) GISTs lacking KIT and PDGFRA gene mutations occasionally occur in adults; primary esophageal GISTs are commonly WT. Case presentation: Herein, we report the case of a 41-year-old female patient who presented with a 1-week history of anterior upper chest pain. Chest computed tomography revealed a 3.7 cm × 2.8 cm × 6.7 cm soft tissue mass in the right posterior mediastinum adjacent to the esophagus. The patient underwent thoracoscopic mediastinal tumor resection and was subsequently diagnosed with an esophageal GIST. Neither KIT nor PDGFRA mutations were detected by Sanger sequencing; however, next-generation sequencing (NGS) identified an FGFR2-KIAA1217 gene fusion in the tumor tissue. No relapse was observed in this patient during the 8-month treatment-free follow-up period. Conclusion: To the best of our knowledge, this report is the first to describe an FGFR2-KIAA1217 fusion in a patient with a quadruple WT esophageal GIST. When WT KIT/PDGFRA GISTS are suspected, intensive genetic analysis is recommended, and obtaining a better molecular characterization of these tumours might reveal novel therapeutic avenues.

Identification of a novel partner gene, KIAA1217, fused to RET: Functional characterization and inhibitor sensitivity of two isoforms in lung adenocarcinoma.

REarranged during Transfection (RET) fusion genes are detected in approximately 1% of lung adenocarcinomas and known primarily as oncogenic driver factors. Here, we found a novel RET fusion gene, KIAA1217-RET, and examined the functional differences of RET51 and RET9 protein, fused with KIAA1217 in cancer progression and drug response. KIAA1217-RET, resulting from the rearrangement of chromosome 10, was generated by the fusion of KIAA1217 exon 11 and RET exon 11 from a non-small cell lung cancer patient. Expression of this gene led to increased cell growth and invasive properties through activations of the PI3K/AKT and ERK signaling pathways and subsequently enabled oncogenic transformation of lung cells. We observed that cells expressing KIAA1217-RET9 fusion protein were more sensitive to vandetanib than those expressing KIAA1217-RET51 and both isoforms attenuated cellular growth via cell cycle arrest. These results demonstrated that KIAA1217-RET fusion represents a novel oncogenic driver gene, the products of which are sensitive to vandetanib treatment, and suggested that the KIAA1217-RET-fusion gene is a promising target for lung cancer treatment.