Kinesin Family Member Research Articles

Retraction

Retraction: “Kinesin family member 2C aggravates the progression of hepatocellular carcinoma and interacts with competing endogenous RNA,” by Guo‐Pei Zhang, Shun‐Li Shen, Yang Yu, Xiao Yue, Wen‐Jie Hu and Shao‐Qiang Li, J Cell Biochem. 2020; 4419‐4430: The above article, published online on 14 February 2020 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/full/10.1002/jcb.29665), has been retracted by agreement between the authors, the journal's Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC.The retraction has been agreed after the authors asked to correct the article. An investigation revealed several flaws and inconsistencies between results presented and experimental methods described, thus the editors consider the conclusions of this article to be invalid.

Skin depletion of Kif3a resembles the pediatric atopic dermatitis transcriptome profile.

Skin deficiency of kinesin family member 3A causes disrupted skin barrier function and promotes development of atopic dermatitis (AD). It is not known how well Kif3aK14∆/∆ mice approximate the human AD transcriptome. To determine the skin transcriptomic profile of Kif3aK14∆/∆ mice and compare it with other murine AD models and human AD, we performed RNA-seq of full-thickness skin and epidermis from 3- and 8-week-old Kif3aK14∆/∆ mice and compared the differentially expressed genes (DEGs) with transcriptomic datasets from mite-induced NC/Nga, flaky tail (Tmem79ma/ma Flgft/ft), and filaggrin-mutant (Flgft/ft) mice, as well as human AD transcriptome datasets including meta-analysis derived atopic dermatitis [MADAD] and the pediatric atopic dermatitis [PAD]. We then interrogated the Kif3aK14∆/∆ skin DEGs using the LINCS-L1000 database to identify potential novel drug targets for AD treatment. We identified 471 and 901 DEGs at 3 and 8weeks of age, respectively, in the absence of Kif3a. Kif3aK14∆/∆ mice had 3.5-4.5 times more DEGs that overlapped with human AD DEGs compared to the flaky tail and Flgft/ft mice. Further, 55%, 85% and 75% of 8-week Kif3aK14∆/∆ DEGs overlapped with the MADAD and PAD non-lesional and lesional gene lists, respectively. Kif3aK14∆/∆ mice spontaneously develop a human AD-like gene signature, which better represents pediatric non-lesional skin compared to other mouse models including flaky tail, Flgft/ft and NC/Nga. Thus, Kif3aK14∆/∆ mice may model pediatric skin that is a precursor to the development of lesions and inflammation, and hence may be a useful model to study AD pathogenesis.

Identification of potential biomarkers for diagnosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a high mortality rate owing to its complexity. Identification of abnormally expressed genes in HCC tissues compared to those in normal liver tissues is a viable strategy for investigating the mechanisms of HCC tumorigenesis and progression as a means of developing novel treatments. A significant advantage of the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) is that the data therein were collected from different independent researchers and may be integrated, allowing for a more robust data analysis. Accordingly, in the present study, the gene expression profiles for HCC and control samples were downloaded from the GEO and TCGA. Functional enrichment analysis was performed using a Metascape dataset, and a protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/proteins (STRING) online database. The prognostic value of mRNA for HCC was assessed using the Kaplan-Meier Plotter, a public online tool. A gene mRNA heatmap and DNA amplification numbers were obtained from cBioPortal. A total of 2,553 upregulated genes were identified. Functional enrichment analysis revealed that these differentially expressed genes (DEGs) were mainly accumulated in metabolism of RNA and the cell cycle. Considering the complexity and heterogeneity of the molecular alterations in HCC, multiple genes for the prognostication of patients with HCC are more reliable than a single gene. Thus, the PPI network and univariate Cox regression analysis were applied to screen candidate genes (small nuclear ribonucleoprotein polypeptide B and B1, nucleoporin 37, Rac GTPase activating protein 1, kinesin family member 20A, minichromosome maintenance 10 replication initiation factor, ubiquitin conjugating enzyme E2 C and hyaluronan mediated motility receptor) that are associated with the overall survival and progression-free survival of patients with HCC. In conclusion, the present study identified a set of genes that are associated with overall survival and progression-free survival of patients with HCC, providing valuable information for the prognosis of HCC.

Vangl2 participates in the primary ciliary assembly under low fluid shear stress in hUVECs.

The pattern of blood fluid shear stress (FSS) is considered the main factor that affects ciliogenesis in human umbilical vein endothelial cells (hUVECs), the underlying mechanism is unclear. Microfluidic chamber experiments were carried out to load hUVECs with low fluid shear stress (LSS, 0.1 dynes/cm2) or high fluid shear stress (HSS, 15 dynes/cm2). Van Gogh2 (Vangl2), a core protein in the planar cell polarity (PCP) pathway, was silenced and overexpressed in hUVECs. Immunofluorescence analysis showed that primary cilia assemble under LSS while disassembling under HSS. Vangl2 expression was consistent with cilia assembly, and its localization showed a polar distribution under LSS. Furthermore, the average number of ciliated cells and primary cilia length were increased in the Vangl2 overexpressing cell lines (the OE group) but decreased in the Vangl2 silenced cell lines (the SH group). When these cells were loaded with different FSS, more ciliated cells with longest primary cilia were observed in the LSS loaded OE group compared with those in the other groups. Immunoprecipitation showed that the interaction between Bardet-Biedl syndrome8 (BBS8) and Vangl2 was enhanced following LSS loading compared to that under HSS. However, the interactions between phosphorylated dishevelled segment polarity protein 2 (pDvl2), kinesin family member 2a (Kif2a), and polo-like kinase 1 (Plk1) and Vangl2 were restrained following LSS loading. Overall, the results indicated that Vangl2 played a significant role during LSS-induced primary cilia assembly by recruiting BBS to promote the apical docking of basal bodies and by restraining Dvl2 phosphorylation from reducing primary cilia disassembly.

Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex

BackgroundFetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We...

KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway.

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.

KIFC1 promotes aerobic glycolysis in endometrial cancer cells by regulating the c-myc pathway.

Endometrial cancer (EC) is a common gynecological malignant tumor worldwide. It is imperative to study pathogenesis and therapeutic targets for improving the prognosis of EC. The present study aimed to explore the function and mechanism of kinesin family member C1 (KIFC1) in EC. EC tumor and adjacent normal tissues were collected from 68 pairs of patients. The expression of KIFC1 in tissues and EC cells was analyzed by immunohistochemistry, qRT-PCR or western blot. MTT assay was used to test the cell viability. Flow cytometry was used to determine apoptosis and the cell cycle. Glucose uptake, lactate production, ATP contents and lactate dehydrogenase (LDH) activity were evaluated by a glucose metabolism kit. The expression of HMGA1, c-myc and glycolytic genes was assessed using western blot or qRT-PCR. A mouse xenograft model was established in BALB/c mice to detect tumor growth in vivo. KIFC1 was significantly upregulated in EC tumor tissues compared to adjacent normal control tissues. The upregulated expression of KIFC1 was correlated with poor prognosis in patients. Lentiviral-mediated overexpression of KIFC1 observably enhanced cell viability and reduced the apoptotic rate of Ishikawa and HEC-1B cells. Cell cycle progression was also expedited in the KIFC1 vector group. Moreover, overexpression of KIFC1 elevated glucose uptake, lactate production, ATP contents and LDH activity. However, knockdown of KIFC1 by short hairpin RNA (shRNA) showed the reverse effect on cellular functions. In addition, the expression of c-myc, GLUT1, LDHA and HK2 was increased by the KIFC1 vector. Moreover, HMGA1 regulated the expression of c-myc and glycolytic genes. Upregulated HMGA1 could rescue the effect of KIFC1 knockdown on cellular functions and the expression of glycolytic genes. Finally, KIFC1 knockdown inhibits tumor growth in vivo. The upregulation of KIFC1 was correlated with poor prognosis in EC. KIFC1 promoted aerobic glycolysis in endometrial cancer cells by regulating the HMGA1/c-myc pathway. KIFC1 may be a potential target for the diagnosis and therapy of EC.

Mitotic WNT: aligning chromosomes through KIF2A

ABSTRACT WNT signaling regulates cell cycle progression and fate determination through β-catenin dependent transcription, and its misregulation is often associated with tumorigenesis. Our recent work demonstrated that basal WNT activity is also required to ensure proper chromosome alignment during mitosis through the regulation of kinesin family member 2A (KIF2A).

Establishment of myoblast cell line and identification of key genes regulating myoblast differentiation in a marine teleost, Sebastes schlegelii.

Skeletal myoblasts are activated satellite cells capable of proliferation and differentiation. Studies on mammalian myoblast differentiation and myogenesis could be carried out in vitro thanks to the availability of mouse myoblast cell line C2C12. Lacking of muscle cell line hinders the studies of teleost fish myogenesis. Here, we established a continuous skeletal muscle cell line from juvenile rockfish (Sebastes schlegelii) muscle using explant method and subcultured more than 50 passages for over 150days. Stable expression of myoblast-specific marker, MyoD (myoblast determination protein) and the potential of differentiation into multi-nucleated skeletal myotubes upon induction suggested the cell line were predominately composed of myoblasts. Transcriptome analysis revealed a total of 4375 genes differentially expressed at four time points after the switch to differentiation medium, which were mainly involved in proliferation and differentiation of myoblasts. KIF22 (kinesin family member 22) and POLA1 (DNA polymerase alpha 1) were identified as the key genes involved in fish myoblast proliferation whereas MYL3 (myosin light chain 3) and TNNT2 (troponin T2) were determined as the crucial genes responsible for differentiation. In all, the continuous myoblasts cultured in this study provided a cell platform for future studies on marine fish myoblast differentiation and myogenesis. The molecular process of myoblast differentiation revealed in this study will open a window into the understanding of indeterminate muscle growth of large teleost.

M304 KIF3A MUTATION IN A 9-MONTH-OLD MALE WITH SEVERE ATOPIC DERMATITIS AND FOOD INTOLERANCE

Single nucleotide polymorphisms (SNPs) in the Kinesin Family Member 3A (KIF3A) gene are associated with asthma and atopic dermatitis (AD). This case presents a novel KIF3A gene mutation in a patient with AD.

Bioinformatics analysis and experimental validation of differentially expressed genes in mouse articular chondrocytes treated with IL-1β using microarray data.

Osteoarthritis (OA) is the most prevalent chronic degenerative disease that affects the health of the elderly. The present study aimed to identify significant genes involved in OA via bioinformatics analysis. A gene expression dataset (GSE104793) was downloaded from the Gene Expression Omnibus. Bioinformatics analysis was then performed in order to identify differentially expressed genes (DEGs) between untreated chondrocytes and chondrocytes cultured with interleukin-1β (IL-1β) for 24 h. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using Metascape. A protein-protein interaction network of DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes. Gene set enrichment analysis (GSEA) was performed using GSEA software. Furthermore, chondrocytes were extracted and treated with IL-1β (10 ng/ml) for 24 h, and reverse-transcription quantitative PCR was used to confirm differential expression of hub genes. Patient samples were also collected to verify the bioinformatic analysis results. Based on the cut-off criteria used for determination of the DEGs, a total of 844 DEGs, including 498 upregulated and 346 downregulated DEGs, were identified. The DEGs were mainly enriched in the GO terms and KEGG pathways ‘inflammatory response’, ‘negative regulation of cell proliferation’, ‘ossification’, ‘taxis’, ‘blood vessel morphogenesis’, ‘extracellular structure organization’, ‘mitotic cell cycle process’ and ‘TNF signaling pathway’. The majority of the PCR results, namely the differential expression of kininogen 2, complement C3, cyclin B1, cell division cycle 20, cyclin A2, 1-phosphatidylinositol 4-kinase, BUB1 mitotic checkpoint serine/threonine kinase, kinesin family member 11, cyclin B2 and BUB1 mitotic checkpoint serine/threonine kinase B were consistent with the bioinformatics results. Collectively, the present observations provided a regulation network of IL-1β-stimulated chondrocytes, which may provide potential targets of OA therapy.

Screening and predicted value of potential biomarkers for breast cancer using bioinformatics analysis

Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women. Increasing molecular targets have been discovered for breast cancer prognosis and therapy. However, there is still an urgent need to identify new biomarkers. Therefore, we evaluated biomarkers that may aid the diagnosis and treatment of breast cancer. We searched three mRNA microarray datasets (GSE134359, GSE31448 and GSE42568) and identified differentially expressed genes (DEGs) by comparing tumor and non-tumor tissues using GEO2R. Functional and pathway enrichment analyses of the DEGs were performed using the DAVID database. The protein–protein interaction (PPI) network was plotted with STRING and visualized using Cytoscape. Module analysis of the PPI network was done using MCODE. The associations between the identified genes and overall survival (OS) were analyzed using an online Kaplan–Meier tool. The redundancy analysis was conducted by DepMap. Finally, we verified the screened HUB gene at the protein level. A total of 268 DEGs were identified, which were mostly enriched in cell division, cell proliferation, and signal transduction. The PPI network comprised 236 nodes and 2132 edges. Two significant modules were identified in the PPI network. Elevated expression of the genes Discs large-associated protein 5 (DLGAP5), aurora kinase A (AURKA), ubiquitin-conjugating enzyme E2 C (UBE2C), ribonucleotide reductase regulatory subunit M2(RRM2), kinesin family member 23(KIF23), kinesin family member 11(KIF11), non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG), ZW10 interactor (ZWINT), and denticleless E3 ubiquitin protein ligase homolog(DTL) are associated with poor OS of breast cancer patients. The enriched functions and pathways included cell cycle, oocyte meiosis and the p53 signaling pathway. The DEGs in breast cancer have the potential to become useful targets for the diagnosis and treatment of breast cancer.

KIFC1 Is Associated with Basal Type, Cisplatin Resistance, PD-L1 Expression and Poor Prognosis in Bladder Cancer.

Kinesin family member C1 (KIFC1), a minus end-directed motor protein, is reported to play an essential role in cancer. This study aimed to analyze KIFC1 expression and examine KIFC1 involvement in cisplatin resistance in bladder cancer (BC). Immunohistochemistry showed that 37 of 78 (47.4%) BC cases were positive for KIFC1. KIFC1-positive cases were associated with high T stage and lymph node metastasis. Kaplan-Meier analysis showed that KIFC1-positive cases were associated with poor prognosis, consistent with the results from public databases. Molecular classification in several public databases indicated that KIFC1 expression was increased in basal type BC. Immunohistochemistry showed that KIFC1-positive cases were associated with basal markers 34βE12, CK5 and CD44. KIFC1 expression was increased in altered TP53 compared to that in wild-type TP53. Immunohistochemistry showed that KIFC1-positive cases were associated with p53-positive cases. P53 knockout by CRISPR-Cas9 induced KIFC1 expression in BC cell lines. Knockdown of KIFC1 by siRNA increased the sensitivity to cisplatin in BC cells. Kaplan-Meier analysis indicated that prognosis was poor among KIFC1-positive BC patients treated with cisplatin-based chemotherapy. Immunohistochemistry showed that KIFC1-positive cases were associated with PD-L1-positive cases. High KIFC1 expression was associated with a favorable prognosis in patients treated with atezolizumab from the IMvigor 210 study. These results suggest that KIFC1 might be a promising biomarker and therapeutic target in BC.

KIF22 promotes bladder cancer progression by activating the expression of CDCA3.

Bladder cancer is a common malignant tumor of the urinary system and is associated with a high morbidity and mortality, due to the difficulty in the accurate diagnosis of patients with early-stage bladder cancer and the lack of effective treatments for patients with advanced bladder cancer. Thus, novel therapeutic targets are urgently required for this disease. Kinesin family member 22 (KIF22) is a kinesin-like DNA binding protein belonging to kinesin family, and is involved in the regulation of mitosis. KIF22 has also been reported to promote the progression of several types of cancer, such as breast cancer and melanoma. The present study demonstrates the high expression of KIF22 in human bladder cancer tissues. KIF22 was found to be associated with clinical features, including clinical stage (P=0.003) and recurrence (P=0.016), and to be associated with the prognosis of patients with bladder cancer. Furthermore, it was found that KIF22 silencing inhibited the proliferation of bladder cancer cells in vitro and tumor progression in mice. Additionally, it was noted that KIF22 transcriptionally activated cell division cycle-associated protein 3 expression, which was also confirmed in tumors in mice. Taken together, the present study investigated the molecular mechanisms underlying the promotion of bladder cancer by KIF22 and provide a novel therapeutic target for the treatment of bladder cancer.

KIF2C Is a Novel Prognostic Biomarker and Correlated with Immune Infiltration in Endometrial Cancer.

Endometrial cancer (EC) is commonly diagnosed cancer in women, and the prognosis of advanced types of EC is extremely poor. Kinesin family member 2C (KIF2C) has been reported as an oncogene in cancers. However, its pathophysiological roles and the correlation with tumor-infiltrating lymphocytes in EC remain unclear. The mRNA and protein levels of KIF2C in EC tissues were detected by qRT-PCR, Western blot (WB), and IHC. CCK8, Transwell, and colony formation assay were applied to assess the effects of KIF2C on cell proliferation, migration, and invasion. Cell apoptosis and cell cycle were analyzed by flow cytometry. The antitumor effect was further validated in the nude mouse xenograft cancer model and humanized mouse model. KIF2C expression was higher in EC. Knockdown of KIF2C prolonged the G1 phases and inhibited EC cell proliferation, migration, and invasion in vitro. Bioinformatics analysis indicated that KIF2C is negatively correlated with the infiltration level of CD8+ T cells but positively with the poor prognosis of EC patients. The apoptosis of CD8+ T cell was inhibited after the knockdown of KIF2C and was further inhibited when it is combined with anti-PD1. Conversely, compared to the knockdown of KIF2C expression alone, the combination of anti-PD1 further promoted the apoptosis of Ishikawa and RL95-2 cells. Moreover, the knockdown of KIF2C inhibited the expression of Ki-67 and the growth of tumors in the nude mouse xenograft cancer model. Our study found that the antitumor efficacy was further evaluated by the combination of anti-PD1 and KIF2C knockdown in a humanized mouse model. This study indicated that KIF2C is a novel prognostic biomarker that determines cancer progression and also a target for the therapy of EC and correlated with tumor immune cells infiltration in EC.

Activation of the TGF-β1/Smad signaling by KIF2C contributes to the malignant phenotype of thyroid carcinoma cells

Kinesin family member 2C (KIF2C) has been identified as a potential oncogene in various types of human cancers; however, the role of KIF2C in thyroid cancer has not yet been elucidated. Quantitative real-time polymerase chain reaction and western blotting were employed for gene expression analysis. Cell Counting Kit-8 and ethynyl-2′-deoxyuridine assays were performed to examine cell proliferation. Cell migration and invasion were assessed by wound-healing and transwell invasion assays. Results showed that KIF2C expression was upregulated in thyroid carcinoma cell lines. In addition, upregulation of KIF2C promoted the proliferation, migration, and invasion of thyroid carcinoma cells, while downregulation of KIF2C exerted the opposite effects. Overexpression of KIF2C induced the activation of transforming growth factor-β1 (TGF-β1)/Smad signaling in thyroid carcinoma cells. However, inhibition of TGF-β1/Smad signaling through silencing TGF-β1 attenuated the promoting effects of KIF2C overexpression on the malignant phenotype of thyroid carcinoma cells. Besides, overexpression of TGF-β1 suppressed the inhibitory effect of KIF2C knockdown on the proliferation and metastasis of thyroid carcinoma cells. In conclusion, our findings demonstrated that KIF2C contributed to the malignant phenotype of thyroid carcinoma cells by inducing the activation of TGF-β1/Smad signaling, thus uncovering a novel mechanism for thyroid carcinoma progression.

Enhanced expression of KIF4A in osteosarcoma predicts a poor prognosis and facilitates tumor growth by activation of the MAPK pathway.

The present study aimed to explore the prognostic value and role of kinesin family member 4A (KIF4A) expression in human osteosarcoma. KIF4A expression was evaluated in human osteosarcoma tissues from The Cancer Genome Atlas and Gene Expression Omnibus datasets. Reverse transcription-quantitative PCR was then applied to assess KIF4A level in both osteosarcoma cell lines and tissues. The association between KIF4A expression and clinical results in patients with osteosarcoma was detected by survival analysis. MTT assays and colony formation assays were used to evaluate the effects of KIF4A on osteosarcoma cell proliferation. The results indicated that the level of KIF4A was increased and associated with a poor prognosis in osteosarcoma tissues. Knockdown of KIF4A was shown to inhibit osteosarcoma cellular proliferation by affecting the MAPK pathway. The level of KIF4A was high in the human osteosarcoma tissues and this could be considered as a tumor induction gene, which may be used as an indicator of prognosis.

The motor domain of testis-enriched kinesin KIF9 is essential for its localization in the mouse flagellum.

Kinesin is a molecular motor that moves along microtubules. Testis-enriched kinesin KIF9 (Kinesin family member 9) is localized in the mouse sperm flagellum and is important for normal sperm motility and male fertility; however, it is unclear if the motor domain of KIF9 is involved in these processes. In this study, we substituted threonine of the ATP binding motif in the KIF9 motor domain to asparagine (T100N) in mice using the CRISPR/Cas9 system, which is known to impair kinesin motor activity. T100N mutant mice exhibit reduced sperm motility and male fertility consistent with Kif9 knockout mice. Further, KIF9 was depleted in the spermatozoa of T100N mutant mice although the amounts of KIF9 were comparable between wild-type and T100N mutant testes. These results indicate that the motor domain of KIF9 is essential for its localization in the sperm flagellum.

Sensitivity of eight types of ALK fusion variant to alectinib in ALK-transformed cells

Tyrosine kinase inhibitors of anaplastic lymphoma kinase (ALK-TKIs) including alectinib have been the standard therapy against ALK fusion gene-positive non–small cell lung cancers (NSCLCs). Many ALK fusion variants have been identified in NSCLCs, and the predominant variants are echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) variant 1 (V1), V2 and V3a/b. However, there have been conflicting reports on the clinical responses of these variants to ALK-TKIs, and there are few reports on other less common ALK variants. To examine the influence of ALK variants on the efficacy of ALK-TKIs, we analyzed the sensitivity to alectinib of eight types of ALK variant: three major variants (V1, V2 and V3a) and five less common variants (V4; kinesin family member 5-ALK; kinesin light chain 1-ALK; striatin, calmodulin-binding protein-ALK; and tropomyosin-receptor kinase fused gene-ALK). Analysis was done by cell-free kinase assays using the recombinant proteins and by cell, growth assays using murine Ba/F3 cells expressing ALK variants. The kinase activity of each recombinant protein was significantly inhibited by alectinib. Intracellular ALK phosphorylation levels and its downstream signaling mediators, STAT3 and ERK, were suppressed by alectinib in each ALK variant-expressing Ba/F3 cell. Each cellular proliferation was markedly inhibited by alectinib treatment. There was no significant difference in the IC50 values between cells, with a <3.6-fold difference in responsiveness. In conclusion, these eight ALK variants had similar sensitivity to alectinib in vitro, indicating that it may not be possible to predict the response to alectinib just by determination of the ALK variant type in ALK fusion-positive NSCLCs.

KIF18b-dependent hypomethylation of PARPBP gene promoter enhances oxaliplatin resistance in colorectal cancer

As the new platinum drug oxaliplatin has been widely used in clinical treatment of colorectal cancer (CRC), oxaliplatin resistance has become a burning problem. In this study, higher expression of PARP-1 binding protein (PARPBP) was detected in oxaliplatin-resistant CRC (OR-CRC) cells than in non-resistant cells. Further research showed that kinesin family member 18 b (KIF18b) induced the overexpression of PARPBP, sustaining oxaliplatin resistance in OR-CRC cells. Through exploring the PARPBP gene promoter, we found that SP1-recruited DNMT3b methylated PARPBP promoter to suppress transcription in CRC cells, and increased KIF18b attenuated the recruitment of DNMT3b to PARPBP promoter by directly interacting with SP1 in OR-CRC cells. Clinical analysis suggested a positive relationship between KIF18b and PARPBP in CRC tissues and indicated poor prognosis in CRC patients with high level of KIF18b or PARPBP. In summary, KIF18b-induced PARPBP contributes to the resistant phenotype of OR-CRC.