The kinesin superfamily in humans comprises 45 members classified into 14 families, Kinesin-1 to Kinesin-14, according to their structural differences (19). Kinesin family members (KIFs) vary in shape, but share three distinct domains, the head, stalk and tail, which perform different functions during cargo transportation. The head, which is an orbicular domain, is conserved among different KIF members; this domain binds to the MT and regulates movement through two binding sites: One binds the MT and is characterized by a Rossman fold, while the other binds to ATP (20). There are three elements within the ATP-binding site, Switch-I, Switch-II and the P-loop, which are responsible for the hydrolysis of ATP and contribute to the conformational changes of the MT-binding domain (21). The location of the head correlates with the direction of kinesin movement along the MTs. The head domain of Kinesin-1 to Kinesin-12 family members is found in the NH₂-terminal region and moves to the plus ends of MTs; these are called the N-kinesins, whereas Kinesin-14A/B family members are C-kinesins and contain the motor domain at the COOH-terminus and the head for the minus end of the MTs. Kinesin-13 family members are M-kinesins, with the head domain situated in the center of the molecule structure, and these are involved in depolymerizing MTs (9).

In contrast to the conserved head domain, the amino acid sequences in the stalk and tail domains are highly variable (22). Most often, KIFs dimerize with each other to form homo- or heterodimers through the stalk domain, and the dimerization status is determined by the length of this domain. KIFs can also function as monomers. KIFs bind with cargo for its selective transport through the highly variable tail domain and may be accompanied by light chain and/or associated proteins (Fig. 1).

Two mechanisms have been suggested to describe the movements of kinesins: The ‘hand-over-hand’ and ‘inchworm’ models (23). In the ‘hand-over-hand’ model, the front head alternates with the rear one on the MTs to forge ahead, and every step consumes two molecules of ATP. In the ‘inchworm’ model, by contrast, the relative positions of the two heads are maintained, enabling movements of 8 nm for the anterior head (Fig. 2).

KIFs are responsible for the transport of cellular organelles, functional proteins packed in vesicles and macromolecules such as chromosomes to the required destinations; thus, they are vital for protein sorting and appropriate positioning of various biological molecules (24). Owing to these functions, KIFs are involved in numerous diseases. Kinesin-1 has been reported to interact with key molecules such as adenomatous polyposis coli protein participating in the Wnt signaling pathway (25) and GluN2B, which regulates N-methyl-D-aspartate receptor activity (26). Thus, dysregulated Kinesin-1 potentially causes neurological diseases (27). Selective knockout of KIF5B in pancreatic β cells and adipocytes affects insulin and adipokine secretion, which leads to metabolic disorders (28,29). For organelle transport, KIF5B is found to regulate mitochondrial localization and activity (30), and contributes to pathological hypertrophic responses in cardiomyocytes (31). Moreover, during the cell cycle, kinesins are responsible for the formation of the spindle apparatus and the alignment and detachment of chromosomes (32). Modulations in KIF activity could influence the cell cycle and alter the apoptosis level of cells. The dysregulation of kinesins has also been reported to affect cell multiplication and migration, with effects on the carcinogenesis of various cancer types, including breast and lung cancer (33,34).

The Kinesin-3 family is distinguished from conventional kinesins by a peculiar neck region containing a β-sheet and a helix (35), and by the incorporation of a forkhead-associated domain in the tail region. Kinesin-3 motors are essential for organelle transport and cytokinesis, which suggest potential roles of kinesin-3 family members in modulating the cell cycle (36).

KIF14, a member of the Kinesin-3 family, serves as a mitotic kinesin and is encoded by a gene situated on chromosome 1q32.1 (37). In CRC, Wang et al (17) found that elevated KIF14 levels contributed to cell proliferation. Flow cytometry results showed that high KIF14 expression could cause G₀/G₁ arrest, indicating a role in the modulation of the cell cycle. Additional experiments confirmed that high KIF14 expression increased the phosphorylation of protein kinase B (also known as Akt), thereby advancing the cell cycle to promote tumorigenesis. This study also demonstrated that microRNA such as miR-200c might directly bind to the 1402- to 1409-bp locus of KIF14; thus, miR-200c could negatively regulate KIF14 function to inhibit overgrowth of cells at the post-transcriptional level.

Kinesin-4 motors participate in the transportation of organelles and in chromosome dynamics, and are vital to the regulation of cycle phase transitions during mitosis (38). In vertebrates, the Kinesin-4 family has five members (KIF4, KIF7, KIF21, KIF27 and NcKIF21A) and KIF4A plays a significant role in the cell cycle (32,38).

KIF4A forms part of the chromosome condensation and separation machinery (38), and the disordered function of KIF4A affects cell division and chromosome integrity. Hou et al (9) described the marked upregulation of KIF4A and its association with the poor survival rate of patients with CRC. Using Transwell assays, high expression of KIF4A increased the migration of CRC cells and their invasion abilities. Given the role of KIF4A in mitosis, cell cycle analysis was performed. The study showed an accumulation of cells in the G₀/G₁ phase when KIF4A expression was decreased. Subsequent assays confirmed that KIF4A could accelerate the multiplication of cancer cells by negatively modulating the promoter of the p21 gene (39). p21 is downstream of p53 and serves as a tumor suppressor regulating G₀/G₁ arrest. Matsumoto et al (8) showed that KIF4A also affected the lymph node metastasis of CRC cells. However, KIF4A was not involved in tumor status, venous invasion or liver metastasis, and did not influence the overall survival rate.

Homotetrameric kinesin-5 motors have vital roles in the cell cycle via regulation of spindle formation (40). Thus, Kinesin-5 family members are essential for cell growth and multiplication (41).

Cancer stem cells (CSCs) are involved in the initiation of carcinoma cell growth and tumorigenesis (42). Imai et al (43) detected a significantly upregulated level of KIF11 in gastric cancer (GC) and showed that KIF11 was correlated with the activity of CSCs in GC. A subsequent study used spheroid colony formation assays to measure how KIF11 expression affected the stemness of CRC cells (16). In CRC cells, the KIF11 defect markedly decreased the number and dimension of spheres, indicating an important role of KIF11. However, phenotypic studies indicated that there were no correlations between KIF11 and clinicopathological characteristics.

Categorized as an N-type kinesin, Kinesin-6 family members have a conventional structure and are involved in cytokinesis and spindle arrangement (44). This family comprises three proteins, KIF20A, KIF20B and KIF23, two of which have been reported to correlate with CRC progression (12,15).

KIF20A is localized in the Golgi apparatus and is responsible for the converse conveyance of Golgi membranes. Upregulation of KIF20A has been observed in some malignant carcinomas (45). With regard to CRC, Xiong et al (15) demonstrated that KIF20A was upregulated in CRC cells and promoted tumor growth in vivo. From data extracted by the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/) and The Cancer Genome Atlas (TCGA; http://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga), it was found that elevated expression of KIF20A was associated with the poor survival rate of patients with CRC. Furthermore, deficient KIF20A expression could increase the apoptosis of cancer cells after treatment with fluorouracil and oxaliplatin. By contrast, the overexpression of KIF20A via transfection was associated with the downregulation of apoptosis-related proteins, which provided evidence that KIF20A affected the chemoresistance of CRC cells. Notably, this study also showed that increased KIF20A expression contributed to the increased phosphorylation of JAK2 and STAT3. Interference with the JAK2/STAT3 pathway markedly prohibited CRC cell proliferation and reversed the decrease in apoptosis of CRC cells stimulated by the dysregulation of KIF20A. Thus, KIF20A was proposed to promote CRC carcinogenesis by activating the JAK2/STAT3 signaling pathway.

Lin et al (12) found that silencing KIF20B decreased the migration and invasion abilities of cancer cells, and had effects on the expression of the epithelial-mesenchymal transition (EMT)-associated transcription factors Snail and Twist. Subsequent experiments showed that the decrease in glioma-associated oncogene 1 (Gli1) expression was associated with impaired KIF20B expression, while the overexpression of Gli1 could relieve the loss of migration ability of CRC cells resulting from the silencing of KIF20B. Gli1 can activate EMT, thereby promoting cancer metastasis (46). Thus, KIF20B was speculated to stimulate Gli1-mediated EMT. The latter experiments performed by Lin et al (12) also revealed the significance of KIF20B in the formation of cell pseudopod protrusions and actin cytoskeleton dynamics. An evaluation of clinical data found that KIF20B was associated with tumor status and metastasis, and its high expression was correlated with the poor overall survival rate of patients with CRC.

Kinesin-8 is indispensable for appropriate allocation of chromosomes in several animal species (47,48). Members of the Kinesin-8 family can modify spindle activity and participate in the segregation of chromosomes (49).

A member of the Kinesin-8 family, KIF18A, serves as an MT depolymerase and plays an important role in chromosome agglutination (50). Nagahara et al (10) showed that increased KIF18A expression notably increased the proliferation, migration and invasion abilities of CRC cells. Zhu et al (51) confirmed that overexpression of KIF18A could accelerate tumor growth in chronic colitis. By contrast, silencing the gene encoding KIF18A increased the apoptosis of tumor cells, which was further confirmed by the observation of the elevated expression of caspase-3 (51). Immunohistochemical assays showed that the phosphorylation level of Akt was significantly decreased in kif18a^−/− dysplasia compared with that in the wild-type (51). These data indicated that KIF18A promotes CRC progression and influences apoptosis by regulating Akt signaling.

The Kinesin-10 subfamily in humans has a single member termed KIF22, which is also known as Kinesin-like 4 (KNSL4)/Kinesin-like DNA binding protein. KIF22 is a chromokinesin that participates in regulating chromosome dynamics during mitosis (52). KIF22 has two nuclear localization sequences (53) and possesses a helix-hairpin-helix DNA-binding motif feature, which contributes to its activity as a transcription factor and the regulation of gene expression (54). The expression of KIF22 has been reported to be upregulated in CRC, and is correlated with tumor stages, rather than with lymph node metastasis or tumor differentiation (14). In addition, interference with KIF22 expression by short hairpin RNA inhibited cell proliferation in vitro and xenograft tumor growth in in vivo models (14). Since it has been reported that KIF22 modulates the expression of CDC25C, a gene involved in the regulation of CDK1 activity and control of mitosis (55), it is quite possible that KIF22 promotes CRC cell proliferation by regulating CDC25C/CDK1 activity.

Characterized by the presence of a divergent catalytic core, Kinesin-11 proteins are distinct from other kinesins and play a role in signal transduction pathways (56).

KIF26B, encoded by a gene situated on the chromosome region lq44 (57), is located downstream of the zinc finger protein Stall1. Wang et al (13) identified a marked upregulation of KIF26B in CRC cells and reported that the expression of KIF26B was associated with tumor size, tumor status and histological differentiation. Survival analyses showed that a high expression level of KIF26B led to low overall survival rate and was a biomarker for a poor prognosis in patients with CRC. Further, defects in KIF26B expression induced a decrease in the expression of cyclin D1 and attenuated CRC cell proliferation.

Members of the Kinesin-13 family function as MT depolymerases, participating in the formation and separation of cilia, as well as the regulation of axon development and rehabilitation (58,59). The proteins of this family are M-type kinesins and include KIF2A, KIF2B, KIF2C/MCAK and KIF24 (35).

KIF2A functions as a MT depolymerase. In CRC, Fan et al (7) analyzed the expression of KIF2A in various tissue samples and observed its significant upregulation in cancer tissues compared with that in normal tissues. Furthermore, KIF2A was correlated with TNM stage and tumor status. Specifically, higher expression of KIF2A correlated with later TNM stages and higher levels of lymph node metastasis. However, no correlations were found between KIF2A expression and preoperative carcinoembryonic antigen level, histological type, tumor location or differentiation. Survival analyses also demonstrated the potential value of KIF2A in predicting a poor prognosis in patients with CRC.

MCAK, encoded by a gene on the chromosomal region 1p34.1 (60), catalyzes the disassembly of MTs from both ends by modulation of mitotic kinases (61). Ishikawa et al (11) found that the overexpression of MCAK mRNA expression could predict lymph node metastasis and could be used as an independent predictor of a poor prognosis in patients with CRC. Furthermore, Ritter et al (18) showed that Aurora B, a vital kinase involved in modulating mitosis, could induce the serine-192-mediated phosphorylation of MCAK to influence its catalytic ability and affect tumor metastasis. Interfering with MCAK phosphorylation led to interference with the transition from prometaphase to metaphase and induced abnormalities in chromosome dynamics. Bioinformatics analysis of a variety of single-nucleotide polymorphisms showed that an E403K mutation could also affect MCAK activity and is crucial for CRC progression (62).

NY-CO-58, which is identical to MCAK and KNSL6 (63), is classified as a tumor antigen and interacts with IgG antibodies in patients with CRC (64). Gnjatic et al (65) observed significant upregulation of NY-CO-58/MCAK expression in CRC samples. Notably, NY-CO-58/MCAK also seemed to influence tumor growth, based on the detection of Ki-67 expression, and could stimulate spontaneous T-cell responses consisting mainly of CD4⁺ T cell-mediated immune reactions. Cytoplasmatic staining indicated that CD4⁺ T cells stimulated by NY-CO-58/MCAK secreted Th1-type cytokines to evoke an immune response, under the regulation of T regulatory cells.