Activation of KIF4A as a Prognostic Biomarker and Therapeutic Target for Lung Cancer

Abstract

Purpose and Experimental Design: To identify molecules that might be useful as diagnostic/ prognostic biomarkers and as targets for the development of new molecular therapies, we screened genes that were highly transactivated in a large proportion of 101lung cancers by means of a cDNA microarray representing 27,648 genes. We found a gene encoding KIF4A, a kinesin family member 4A, as one of such candidates. Tumor tissue microarray was applied to examine the expression of KIF4A protein and its clinicopathologic significance in archival non^small cell lung cancer (NSCLC) samples from 357 patients. A role of KIF4A in cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of KIF4A on mammalian cells was examined using Matrigel assays. Results: Immunohistochemical staining detected positive KIF4A staining in 127 (36%) of 357 NSCLCs and 19 (66%) of 29 small-cell lung cancers examined. Positive immunostaining of KIF4A protein was associated with male gender (P = 0.0287), nonadenocarcinoma histology (P = 0.0097), and shorter survival for patients with NSCLC (P = 0.0005), and multivariate analysis confirmed its independent prognostic value (P = 0.0012). Treatment of lung cancer cells with small interfering RNAs for KIF4A suppressed growth of the cancer cells. Furthermore, we found that induction of exogenous expression of KIF4A conferred cellular invasive activity on mammalian cells. Conclusions: These data strongly implied that targeting the KIF4A molecule might hold a promise for the development of anticancer drugs and cancer vaccines as well as a prognostic biomarker in clinic.

Molecular signatures of thyroid follicular neoplasia

“…In agreement with the clinical experience, we noted that cell-cycle mRNAs followed a gradient ranging from a few fold to more than 50-fold up-regulation, which may limit the isolated use of this parameter for diagnostic purposes. A number of the up-regulated transcripts including anillin , ARP 2/3 complex (Otsubo et al 2004), abnormal spindle homolog (Ayllon & O'connor 2007, Lin et al 2008, centromere protein F (Campone et al 2008), KIF4A (Taniwaki et al 2007), maternal embryonic leucine zipper kinase (Gray et al 2005), NIMA-related kinase 2 (Hayward & Fry 2006), PDZ-binding kinase, protein regulator of cytokinesis 1 (Boukarabila et al 2009), regulator of chromosome condensation 2 (Stacey et al 2008), encoded proteins that are directly involved in mitosis and several of them are over-expressed in other cancers. In particular, transcripts encoding ribonucleotide reductase small subunit, RRM2, and topoisomerase 2a, TOP2A respectively, are intimately connected to cancer.…”

The role of kinesin family proteins in tumorigenesis and progression

“…For example, Narayan et al 49 reported that the expression of KIF4A mRNA in cervical cancer was much higher than that in normal tissues. Taniwaki et al 18 demonstrated that the KIF4A gene was activated in nonsmall cell lung cancer (NSCLC) cells and that treatment of NSCLC cells with specific siRNA to knockdown KIF4A expression resulted in the suppression of cancer cell growth. Moreover, patients with NSCLC who had KIF4A-positive tumors had a shorter cancer-free survival than patients who had KIF4A-negative tumors.…”

“…Alteration of their expression and functions leads to human disease, including cancer development and progression. For example, alterations of KIF3, 13 KIF1B, 14 KIF14, 15 and Kid 16 proteins were observed in breast cancer; KIF14 17 and KIF4A 18 were altered in lung cancer; and KIF1B was down-regulated in neurofibroma. 19 In addition, altered expression of EG5, 20 CENP-E, 21 KIF5B, 22 and KIF18A 23 proteins was associated with the development of different human cancers.…”

“…4 To date, many studies have demonstrated that altered expression of kinesins is associated with the development and progression of various human cancers. [13][14][15][16][17][18][19][20][21][22][23] Abnormal kinesin expression alters the equal distribution of genetic materials during cell mitosis because of chromosome hypercondensation, aberrant spindle formation, anaphase bridges, defective cytokinesis, aneuploidy, Figure 1. The structure and functional domains of kinesin family proteins (KIFs) are illustrated.…”

Kinesin KIF4A is associated with chemotherapeutic drug resistance by regulating intracellular trafficking of lung resistance-related protein

“…KIF4A has been reported to participate in a variety of cell processes, including intracellular trafficking of HIV gag and integrin-β 1 (Martinez et al, 2008;Willemsen et al, 2014), mitotic progression (Zhu and Jiang, 2005;Wandke et al, 2012), DNA damage response (Wu et al, 2008) and brain neuron development (Midorikawa et al, 2006). It has been also reported that KIF4A was upregulated in lung cancer and could serve as a prognostic biomarker and therapeutic target for lung cancer (Taniwaki et al, 2007;Zhu et al, 2015). Our previous studies showed that KIF4A is also involved in cisplatin resistance in lung cancer cells (Xiao et al, 2016).…”