MFAP5 suppression inhibits migration/invasion, regulates cell cycle and induces apoptosis via promoting ROS production in cervical cancer
Authors: Yanqin Zhang
Qingmei Li
Qiuli Jiang
Journal: Biochemical and Biophysical Research Communications (2018)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Apoptosis; MFAP5; Migration/invasion; ROS; cervical cancer.
Affiliations: 2nd Area of Obstetrics, The People's Hospital of Pingyi County, No. 7, Jinhua Road, Pingyi Street, Linyi, 273300, China., Department of Nursing, Yulin Traditional Chinese Medicine Hospital, No. 131 Xinjian South Road, Yuyang District, Yulin, 719000, China., Department of Gynecology, Hanzhong Central Hospital, No.22, Kangfu Road, Hantai District, Hanzhomg, 723000, China. Electronic address: .

Abstract:  Cervical cancer is one of the most lethal types of cancer among female. Microfibrillar-associated protein 5 (MFAP5) is an extracellular matrix (ECM) glycoprotein, and is confirmed to be involved in cell signaling during microfibril assembly, elastinogenesis and cell survival. However, the role of MFAP5 in cervical cancer development and progression remains poorly understood. In the study, MFAP5 was over-expressed in human cervical cancers, and in different cervical cancer cell lines. Patients suffering from cervical cancer with low MFAP5 expression exhibited better survival rate. Suppressing MFAP5 in cervical cancer cells markedly reduced the cell proliferation, migration and invasion by modulating epithelial-mesenchymal transition (EMT)-related signaling pathway. In addition, MFAP5 knockdown induced large number of cells distributed in G2/M phase, along with reduced Cyclin B1, Cyclin D1 and cyclin-dependent kinase 4 (CDK4) expressions, and enhanced p21 and p53 levels. Moreover, apoptosis was highly induced by MFAP5 silence through reducing Bcl-xl and Bcl-2 expressions, and promoting Bax, cleaved Caspase-3 and poly (ADP-Ribose) polymerase (PARP) expressions in cervical cancer cells. Reactive oxygen species (ROS) production levels were also higher in MFAP5-knockdown cells, along with Jun-N-terminal kinase (JNK) activation. Importantly, we found that MFAP5 knockdown-inhibited cervical cancer cell growth was dependent on ROS production. Finally, the depletion of MFAP5 prevented cervical cancer progression in vivo. In summary, our study identified a critical role played by MFAP5 in the progression of cervical cancer and the potential mechanisms by which exerted its effects, indicating that targeting MFAP5-related pathways could be conducive to the therapies for cervical cancer. 

Retracted: No

PubPeer comments:
 **Marian Annett was not marginalised** There are many things about this paper that I could take issue with, but I ll just focus on one aspect. In her evaluation of the rivalry between Chris McManus and Marian Annett, Cornel gives the impression that Annett was oppressed, marginalised, and denied resources, whereas McManus benefitted from being a man with a strong scientific network. This doesn t match my memory of this period of science, and I can supplement my recollections with several pieces of evidence that show that Annett was taken seriously. First, if one looks at objective indicators of the impact of the work of the two scientists, they are closely comparable. A bibliographic search on Web of Science on the topic of handedness OR lateral* with Annett M* as author gives 69 publications, mean citations per publication, 43.06, H-index 29, date range 1964 to 2011. The same search for McManus I* gives 68 publications, mean citations per publication, 31.29, H-index 25, date range 1980 to 2018. Because H-index reflects years since publication, a fairer comparison is just to take papers published in the same year range, though this disadvantages Annett by excluding her early, seminal papers. When we look just at publications between 1980 and 2011, the two researchers are evenly matched: the H-index for Annett is 26 and for McManus is 23. (These again are just for papers on topic of handedness OR lateral*). Furthermore, Web of Science excludes books: according to Google Scholar, Annett s 2002 book,  Handedness and Brain Asymmetry: the Right Shift Theory garnered 682 citations, and the earlier  Left, Right: Hand and Brain had 1,932 citations. In 1995, a special issue of Cahiers de Psychologie Cognitive Current Psychology of Cognition published a target article by Annett on the Right Shift Theory together with 20 commentaries and a final reply by Annett. In 1997, Cognitive Neuropsychiatry featured a target article by Annett on the Right Shift Theory in relation to schizophrenia and autism, with five commentaries, and again, a final summing up by Annett. Next we turn to resources. Both McManus and Annett were unusual in that most of their papers involved analyses of existing datasets, without the involvement of research assistants or collaborators. Nevertheless, Annett did gather empirical data on her peg-moving task, and her publications on these with junior co-authors mention funding by the British Medical Research Council (Annett Ockwell, 1980; Annett Kilshaw, 1984; Annett Manning, 1990) and the Wellcome Trust (Annett, Eglinton Smythe, 1996; Eglinton Annett, 2007). Further evidence of the regard in which Annett was held by the psychology community can be found in her obituary, co-authored by Beaton, Corballis and McManus in 2020. A scientist who received an DSc degree from the University of London, and had a meeting at the British Psychological Society to mark her retirement can hardly be seen as marginalised. I would also take issue with the claim that, in papers criticizing Annett, McManus  mobilised intersectional stereotypes drawing a picture of her as an old(-fashioned), emotional, second-rate scientist. The two critiques Cornel cites, published in 1995 and 1997, contain plenty of negative comments, but the criticism is of lack of agreement between theory and data, not of the person who proposed them. And he is just as vocal in comments on other theorists - see for instance his 1994 critique (with Bryden and Bulman-Fleming) of Geschwind-Behan-Galaburda (all senior males) and 2010 critique of Jones and Martin (male female; same generation as him). As documented by Cornel, McManus also came up against ugly facts that contradicted his own DC model when he had the opportunity to be involved in a genome-wide analysis study of handedness: his response was to accept that a single-gene account of handedness could no longer be sustained. He applied the rule that one needs to test theory against data to himself just as he had done to others. Having observed McManus over many years, I can confirm he is someone who will argue his case forcefully. I can provide an example of his peer review of a paper that I recently published with Tim Bates: https: wellcomeopenresearch.org articles 4-161. His reviews are detailed, scholarly, with many criticisms of our work, but at no point did I have the impression that he was attacking me, as a woman. He was doing what a good reviewer does: revealing underlying weaknesses and suggesting alternative explanations. Addressing his concerns, and those of other reviewers, led to an improvement of our paper. There is no doubt that women are often marginalised in science, and Annett s sex gender will inevitably have played an important part in her career. But the ultimate failure of Annett s Right Shift Theory was not due to neglect of work by an older woman, or biased criticism by McManus, but to the fact that her, admittedly clever, theory was incompatible with empirical data. Cornel appears to use the McManus Annett rivalry as a canvas on which to paint her stereotyped views of male and female scientists, to confirm a world view where men are oppressors and women the oppressed. Facts that do not fit this viewpoint are ignored, leading to a skewed account of the history. **References** Annett, M. (1984). Lateral preference and skill in dyslexics; Implications of the right shift theory. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 25, 357u2013377. https: doi.org 10.1111 j.1469-7610.1984.tb00158.x Annett, M. (1985). Left, Right: Hand and Brain. The Right Shift Theory. Lawrence Erlbaum. Annett, M. (2002). Handedness and Brain Asymmetry: The Right Shift Theory. Routledge. Annett, M., Eglinton, E., Smythe, P. (1996). Types of Dyslexia and the Shift to Dextrality. Journal of Child Psychology and Psychiatry, 37(2), 167u2013180. https: doi.org 10.1111 j.1469-7610.1996.tb01388.x Annett, M., Manning, M. (1990). Reading and a Balanced Polymorphism for Laterality and Ability. Journal of Child Psychology and Psychiatry, 31(4), 511u2013529. https: doi.org 10.1111 j.1469-7610.1990.tb00795.x Annett, M., Ockwell, A. (1980). Birth Order, Birth Stress and Handedness. Cortex, 16(1), 181u2013187. https: doi.org 10.1016 S0010-9452(80)80033-5 Beaton, A. A., Corballis, M., McManus, C. (2020). Obituary for Dr. Marian Annett, 1931u20132018. Laterality, 25(4), 405u2013412. https: doi.org 10.1080 1357650X.2020.1766425 Bryden, M. P., McManus, I. C., Bulman-Fleming, M. B. (1994). Evaluating the empirical support for the Geschwind-Behan-Galaburda model of cerebral lateralization. Brain and Cognition, 26(2), 103u2013167. https: doi.org 10.1006 brcg.1994.1045 Eglinton, E., Annett, M. (2008). Good phonetic errors in poor spellers are associated with right-handedness and possible weak utilisation of visuospatial abilities. Cortex, 44(6), 737u2013745. https: doi.org 10.1016 j.cortex.2007.01.001 McManus, I. C. (1995). Achillesu2019 right heel: The vulnerabilities of the right shift theory. Cahiers de Psychologie Cognitive Current Psychology of Cognition, 14(5), 565u2013574. McManus, I. C. (1997). Autism and schizophrenia are not due to a single genetic locus. Cognitive Neuropsychiatry, 2(3), 226u2013230. McManus, I. C. (2010). Precisely wrong? The problems with the Jones and Martin genetic model of sex differences in handedness and language lateralisation. Cortex, 46(5), 700u2013702. https: doi.org 10.1016 j.cortex.2009.08.008 ,