KIFC3 regulates progression of hepatocellular carcinoma via EMT and the AKT/mTOR pathway

Lu, Shimin; Liu, Yinghui; Tian, Shan; He, Yang; Dong, Weiguo

doi:10.1016/j.yexcr.2023.113564

Cited by 7 publications

(4 citation statements)

References 40 publications

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“…On the opposite trend, MAP1B appeared anticorrelated to epithelial polarity, consistent with its role of microtubule destabilizer and regulator of neuronal cell polarity (Tortosa et al, 2013). Kinesins were distributed all over the graph but, as previously shown, the expressions of KIFC3 and KLC3 showed high and opposite correlation with epithelial polarity: KIFC3 being negatively correlated (Lu et al, 2023) whereas KLC3 was positively correlated to it (Fustaino et al, 2017). Interestingly, three plakins, namely epiplakin (EPPK1), desmoplakin (DSP) and periplakin (PPL) all appeared as clear outliers (Figure 3).…”

Section: Plakins At the Intersection Of Emt Polarity And Microtubulessupporting

confidence: 74%

Plakins are involved in the maintenance of epithelial polarity

Geay,

Margaron,

Gentien

et al. 2023

Preprint

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As epithelia are the interface between the organism and the external environment, they are often subject to damage and must be frequently renewed. However, maintaining epithelial integrity during this renewal is challenging, and loss of cell polarity is a potent inducer of tumorigenesis. In this study, we used transcriptomic data from breast cancer cells at different stages of tumor development to identify molecular changes associated with the early stages of tumor transformation. We correlated these protein expression profiles with either cell polarity defects or cell progression along the epithelial-to-mesenchymal transition (EMT). We identified plakins, namely epiplakin (EPPK1), desmoplakin (DSP) and periplakin (PPL), that were downregulated in cells that had lost their epithelial polarity and also downregulated in cells that had progressed through EMT. We further tested them experimentally by knocking down their expression in a non-tumorigenic epithelial breast cell line (MCF10A). We demonstrated their causal role in the loss of polarity, as revealed by the misorientation of the nuclear centrosome vector. We also found that vimentin, a marker of EMT, was overexpressed in plakin knocked-down cells, suggesting that plakins may have both a structural and a regulatory role in maintaining the epithelial state.

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Section: Plakins At the Intersection Of Emt Polarity And Microtubulessupporting

confidence: 74%

Plakins are involved in the maintenance of epithelial polarity

Geay,

Margaron,

Gentien

et al. 2023

Preprint

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“…On the opposite trend, MAP1B appeared anticorrelated to epithelial polarity, consistent with its role of microtubule destabilizer and regulator of neuronal cell polarity (Tortosa et al., 2013). Kinesins were distributed all over the graph but, as previously shown, the expressions of KIFC3 and KLC3 showed high and opposite correlation with epithelial polarity: KIFC3 being negatively correlated (Lu et al., 2023) whereas KLC3 was positively correlated to it (Fustaino et al., 2017). Interestingly, three plakins, namely epiplakin (EPPK1), desmoplakin (DSP), and periplakin (PPL), displayed high correlation values with both markers (Figure 3): their expressions were negatively correlated to the EMT score of HME and positively correlated to the polarity score of TNBC (Figure S1).…”

Section: Resultsmentioning

confidence: 76%

Plakins are involved in the regulation of centrosome position in polarized epithelial cells

Geay,

Margaron,

Gentien

et al. 2024

Biology of the Cell

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Background InformationThe control of epithelial cell polarity is key to their function. Its dysregulation is a major cause of tissue transformation. In polarized epithelial cells,the centrosome is off‐centred toward the apical pole. This asymmetry determines the main orientation of the microtubule network and intra‐cellular traffic. However, the mechanism regulating centrosome positioning at the apical pole of polarized epithelial cells is still poorly undertood.ResultsIn this study we used transcriptomic data from breast cancer cells to identify molecular changes associated with the different stages of tumour transformation. We correlated these changes with variations in centrosome position or with cell progression along the epithelial‐to‐mesenchymal transition (EMT), a process that involves centrosome repositioning. We found that low levels of epiplakin, desmoplakin and periplakin correlated with centrosome mispositioning in cells that had progressed through EMT or tissue transformation. We further tested the causal role of these plakins in the regulation of centrosome position by knocking down their expression in a non‐tumorigenic breast epithelial cell line (MCF10A). The downregulation of periplakin reduced the length of intercellular junction, which was not affected by the downregulation of epiplakin or desmoplakin. However, down‐regulating any of them disrupted centrosome polarisation towards the junction without affecting microtubule stability.ConclusionsAltogether, these results demonstrated that epiplakin, desmoplakin and periplakin are involved in the maintenance of the peripheral position of the centrosome close to inter‐cellular junctions. They also revealed that these plakins are downregulated during EMT and breast cancer progression, which are both associated with centrosome mispositioning.SignificanceThese results revealed that the down‐regulation of plakins and the consequential centrosome mispositioning are key signatures of disorganised cytoskeleton networks, inter‐cellular junction weakening, shape deregulation and the loss of polarity in breast cancer cells. These metrics could further be used as a new readouts for early phases of tumoral development.

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“…As for KIFC3, another kinesin-14 family member, was reported to promote HCC development via the PI3K/Akt/mTOR signaling axis, and the stimulative action of KIFC3 could be suppressed by addition of LY294002 (a highly selective inhibitor targeting PI3K), and combining with KIFC3-depletion and LY294002 treatment displayed a synergistic inhibitory effect, suggesting the potential therapeutic value of KIFC3 in HCC [ 114 ] (Fig. 5 C).…”

Section: The Roles Of Kifs In Hccmentioning

confidence: 99%

“…According to the IHC intensity of KIFC3 in 36 paired HCC and adjacent normal samples, the abundance of KIFC3 was observed to be up-regulated in tumors with negative consequences for OS of patients with HCC [ 114 ].…”

Section: Kifs In Hcc and Btcs Prognosismentioning

confidence: 99%

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

Zhao,

Li,

Feng

et al. 2024

Biomark Res

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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).

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KIFC3 regulates progression of hepatocellular carcinoma via EMT and the AKT/mTOR pathway

Cited by 7 publications

References 40 publications

Plakins are involved in the maintenance of epithelial polarity

Plakins are involved in the maintenance of epithelial polarity

Plakins are involved in the regulation of centrosome position in polarized epithelial cells

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

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