KIFC1 is activated by TCF-4 and promotes hepatocellular carcinoma pathogenesis by regulating HMGA1 transcriptional activity
Authors: Jingping Yun
Kai Teng
Jun Liu
Miaomiao Dai
Jiewei Chen
Xinyuan Guan
Shi Wei
Kanghua Xiao
Jinbin Chen
Chi Zhang
Dan Xie
Journal: Journal of Experimental & Clinical Cancer Research (2019)
Discipline: CLINICAL MEDICINE
Keywords: HMGA1; Hepatocellular carcinoma; Kinesin family member C1; Pathogenesis; TCF-4.
Affiliations: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. ., Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. .

Abstract:  Background: Kinesins play important roles in the development and progression of many human cancers. The functions and underlying mechanisms of kinesin family member C1 (KIFC1), a member of the kinesin-14 family, in the pathogenesis of hepatocellular carcinoma (HCC) have not been fully elucidated. Methods: In this study, 168 HCC samples were first analyzed to examine the association between KIFC1 expression and patient clinicopathological features and prognosis. The role of KIFC1 in HCC cell proliferation and metastasis was investigated both in vivo and in vitro. The upstream regulation and downstream targets of KIFC1 were studied by qRT-PCR, western blotting, coimmunoprecipitation, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. Results: KIFC1 was highly expressed in HCC tissues and positively associated with advanced stages and poor prognosis. KIFC1 knockdown suppressed HCC cell proliferation and invasion both in vitro and in vivo. Furthermore, KIFC1 knockdown decreased invadopodia formation and reduced epithelial-mesenchymal transition (EMT). HMGA1, an architectural transcriptional factor, was identified to interact with KIFC1. HMGA1 could bind to the promoters of Stat3, MMP2 and EMT-related genes and promote gene transcription. KIFC1 enhanced HMGA1 transcriptional activity and facilitated HCC proliferation and invasion. Moreover, KIFC1 was activated by TCF-4, and KIFC1 inhibition enhanced HCC cell sensitivity to paclitaxel. Conclusions: Our findings suggest that KIFC1, activated by TCF-4, functions as an oncogene and promotes HCC pathogenesis through regulating HMGA1 transcriptional activity and that KIFC1 is a potential therapeutic target to enhance the paclitaxel sensitivity of HCC. 

Retracted: No

PubPeer comments:
 Figure 2 has been corrected without further explanation. It is worth pointing out how the original figure 2 looked like. * Figure 2D: The top three panels all appeared to show areas of overlap (shown with blue, red, and green boxes), suggesting they came from one original sample. * Figure 2D: In the red region, shared in all three photos, a cell is visible in two photos, but not in the third photo. Shown with a blue arrow. ![file] * Figure 2B1: The SNB19 and LN229 panels appeared to look unexpectedly similar. Shown with aqua boxes. ![file] , 
 In addition, and not addressed in the 2013 correction, there are some possible issues with Figure 3. * Figure 3A: Some horizontal and vertical lines visible around some cells. ![file] * Figure 3B and 5. The actin panel look very similar to each other. Shown with red boxes. ![file] * Figure 3B and 5. Two SEPT7 panels appear to look similar. Shown with green boxes. ![file] * Figure 3B and 5. Two MMP2 panels appear to look similar. Shown with purple boxes. ![file] All issues have been reported to the journal in May 2014. , 
 2020 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0228340 After this article [1] was published, a Correction was published [2] to address the following issues involving Fig 2: In Fig 2B1, the plots shown in SNB19 and LN229 control panels appeared similar in the original publication. LN229 Control and Scrambled panels were replaced in the updated version of this figure provided with the Correction. In Fig 2D1, there appeared to be areas of overlap between the images shown in SNB19 Control, Scrambled, and 30a-5p AS panels. The Control and Scrambled panels were replaced in the updated figure provided with the Correction. Additional concerns were subsequently raised about results reported in Figs 3 and 5. Specifically: In Fig 3A, when levels are adjusted there appear to be horizontal and vertical lines or discontinuities around some cells, e.g. in the SNB19, 30a-5p AS CyclinD1 panel and the LN229, Control CyclinD1 panel. The corresponding author provided original images in support of these two panels and clarified that in preparing this figure they moved cell images from within the same original microscopy image, bringing more cells into the fields shown in the figure. There are similarities between the following data in Fig 3B and Fig 5: u25cb. Fig 3B, SNB19 u03b2-actin lanes 2, 3 are similar to Fig 5, LN229 u03b2-actin lanes 4, 3 when flipped horizontally. u25cb. Fig 3B, SNB19 SEPT7 lanes 2, 3 appear similar to Fig 5, LN229 SEPT7 lanes 4, 3, when flipped horizontally. u25cb. Fig 3B, LN229 MMP2 lanes 2, 3 appear similar to Fig 5, SNB19 MMP2 lanes 4, 3, when flipped horizontally. u25cb. Fig 3B LN229 MMP9, lanes 2, 3 appear similar to Fig 5, SNB19 CyclinD1 lanes 4, 3, when flipped horizontally. In response to the western blot concerns, the authors noted that errors were made in preparing the u03b2 -actin panels. They provided a replacement image for Fig 3B SNB19 u03b2 -actin, and they provided western blot images cropped similarly to the published figure panels (although with additional lanes) to support several panels of Figs 3 and 5. No image data were provided to support the following, which include panels for which concerns were raised: Fig 3B, SNB19 cells, SEPT7, MMP2, MMP9; Fig 3B, LN229 cells, MMP9; and Fig 5, LN229 cells, Bcl2. The SNB19 PCNA image provided for Fig 3B differed from the published figure. The original unadjusted and uncropped blot images supporting Figs 3 and 5 are not available. Without the original image data, we are unable to resolve the above concerns or verify the reported results. In light of the above concerns, the PLOS ONE Editors retract this article. In our discussion of this case, the authors clarified that in the Correction [2], the updated figure panels reported data from the original experiments. The original underlying data for Fig 2 are no longer available. The authors either could not be reached or did not reply to the retraction notification. References 1.Jia Z, Wang K, Wang G, Zhang A, Pu P (2013) MiR-30a-5p Antisense Oligonucleotide Suppresses Glioma Cell Growth by Targeting SEPT7. PLoS ONE 8(1): e55008. https: doi.org 10.1371 journal.pone.0055008 pmid:23383034 2.Jia Z, Wang K, Wang G, Zhang A, Pu P (2013) Correction: MiR-30a-5p Antisense Oligonucleotide Suppresses Glioma Cell Growth by Targeting SEPT7. PLoS ONE 8(10): https: doi.org 10.1371 annotation 9a8447a4-bffe-445f-b323-7e200896aea9 ,