The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside

Abstract

As a major component of the digestive system malignancies, tumors originating from the hepatic and biliary ducts seriously endanger public health. The kinesins (KIFs) are molecular motors that enable the microtubule-dependent intracellular trafficking necessary for mitosis and meiosis. Normally, the stability of KIFs is essential to maintain cell proliferation and genetic homeostasis. However, aberrant KIFs activity may destroy this dynamic stability, leading to uncontrolled cell division and tumor initiation. In this work, we have made an integral summarization of the specific roles of KIFs in hepatocellular and biliary duct carcinogenesis, referring to aberrant signal transduction and the potential for prognostic evaluation. Additionally, current clinical applications of KIFs-targeted inhibitors have also been discussed, including their efficacy advantages, relationship with drug sensitivity or resistance, the feasibility of combination chemotherapy or other targeted agents, as well as the corresponding clinical trials. In conclusion, the abnormally activated KIFs participate in the regulation of tumor progression via a diverse range of mechanisms and are closely associated with tumor prognosis. Meanwhile, KIFs-aimed inhibitors also carry out a promising tumor-targeted therapeutic strategy that deserves to be further investigated in hepatobiliary carcinoma (HBC).

Keywords: Hepatobiliary carcinoma; Kinesin; Prognosis assessment; Signaling transduction; Targeted therapy.

Fig. 1

Overall landscape of kinesin superfamily. Genes for 45 different kinesins belonging to 14 subfamilies have been identified in the murine and human genomes. Kinesin structure incorporates four primary domains: head, neck, stalk, and tail. The amino and carboxyl termini are labeled

Fig. 2

The roles of the kinesin-2, 3, 4 family members in HCC. (A) Kinesin-2 family: KIF3B may influence tumor cells proliferation and apoptosis via an effect on Akt signaling pathway. (B) Kinesin-3 family: Tumor promotion: a positive feedback loop has been described between KIF14 and ETS1 in Akt signaling transduction. Transcription factor ETS1 up-regulates KIF14 expression, and KIF14 promotes tumor development by stimulating Akt signaling, which subsequently activates ETS1 to further magnify this effect. Both sorafenib treatment, KIF14 interference, and transcriptional suppression by Sox17 can disrupt the cycle by inhibiting KIF14 expression. Moreover, the tumor promotion mediated by KIF14 may also be correlated with post-translational modification (ubiquitination) of p27^Kip1. Tumor suppression: the single nucleotide polymorphism (SNP) of KIF1B (represented by rs17401966) has been reported to protect against HCC. (C) Kinesin-4 family: KIF4A protects tumor cells from apoptosis by stimulating PI3K/Akt signaling, and both FOXM1c and hepatitis B virus (HBV) can positively regulate KIF4A expression at the transcriptional level. And two underlying associations: KIF4A and p53 signaling, KIF21B and tumor cell proliferation and survival, remain to be further investigated

Fig. 3

The roles of the kinesin-5, 6 family members in HCC. (A) Kinesin-5 family: a reciprocal feedback loop exists between KIF11 and PAK6 and impacts tumor proliferation, invasion, and migration, both PAK6-inhibition or KIF11-overexpression can enhance tumor cells motility and viability. Similarly, the abnormal spindle-like microcephaly-associated protein (ASPM) also negatively modulates KIF11 expression, and the regulatory effects of the ASPM/KIF11 signaling on tumor proliferation, invasion, and migration may be linked to WNT/β-catenin signaling transduction. (B) Kinesin-6 family: For KIF20A, identified as an effector in the Hedgehog (Hh) signaling that could be indirectly transcriptional up-regulated by Gli2, acting via FOXM1. For KIF23, exerted as an up- or downstream regulator of three major axes including YAP/TAZ, p53, and WNT/β-catenin signaling pathways with an impact on HCC. Besides, KIF23 could also be recognized and repressed by miR-424-5p, or inhibited by FOXM1 silencing, which was attributed to reduced acetylation level of histone H3 lysine 27 (H3K27ac) at the promoter of KIF23

Fig. 4

The roles of the kinesin-7, 8, 11 family members in HCC

Fig. 5

The roles of the kinesin-12, 13, 14 family members in HCC. (A) Kinesin-12 family: KIF15 interacts with proteasome 26 S subunit, non-ATPase 12 (PSMD12) and is stimulated by it. And the regulative impacts of KIF15 on HCC cells growth, proliferation, migration, and chemo-resistance have been linked to the MEK/ERK signaling. Furthermore, KIF15 also eliminates intracellular reactive oxygen species (ROS) accumulation and facilitates tumor stem cell phenotype by interacting with phosphoglycerate dehydrogenase (PHGDH) and stabilizing its expression via inhibiting proteasomal degradation. (B) Kinesin-13 family: KIF2C mediated cross-talk between WNT/β-catenin and mTORC1 signaling: WNT/β-catenin signaling caused transcriptional up-regulation of KIF2C when TCF4 bound to the KIF2C promoter. Subsequently, KIF2C interacted with TBC1D7 causing destabilization of TSC1/2 and reduced the anti-oncogenic effect of TSC2 on mTORC1 signaling transduction, finally promoted tumor development. Moreover, the pro-tumor impacts of KIF2C might also be attributed to its latent regulatory function in the Ras/MAPK and MEK/ERK signaling axes. Another family member KIF2A, negatively regulated by miR-424-5p, has also been demonstrated to facilitate malignant progression via the Notch 1 signaling, in which KIF2A interacts with Notch 1 and positively regulates its expression. (C) Kinesin-14 family: Similar to KIF2C, KIFC1 can also be transcriptionally up-regulated by TCF4, and aberrant activation of KIFC1 facilitates HCC progression through enhancing the transcriptional activity of High Mobility Group AT-Hook 1 (HMGA1), which regulates several cancer-related genes transcription (including STAT3, MMP2, E-cadherin, Vimentin, Twist1) by binding to their corresponding promoter regions. Besides, KIFC1 also participates in the stimulation of PI3K/Akt signaling via up-regulating the expression of gankyrin. Similarly, miR-532-3p plays an inhibitory role in this process by directly suppressing KIFC1 expression. As for KIFC3, it has also been demonstrated to stimulate HCC development through activating PI3K/Akt/mTOR signaling pathway

Fig. 6

The roles of the kinesin members in biliary tract carcinomas (BTCs)