Downregulation of nicotinamide N-methyltransferase inhibits migration and epithelial-mesenchymal transition of esophageal squamous cell carcinoma via Wnt/β-catenin pathway
Authors: Fangxia Guan
Shanshan Ma
Wenjie Wang
Yanyan Cui
Luyu Zhang
Yanting Zhang
Hongtao Liu
Xingxing Zang
Journal: Molecular and Cellular Biochemistry (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Epithelial-mesenchymal transition (EMT); Esophageal squamous cell carcinoma (ESCC); Metastasis; Nicotinamide N-methyltransferase (NNMT); Wnt/β-catenin.
Affiliations: College of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China., Department of Microbiology and Immunology, Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York, NY, 10461, USA., College of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China. ., Henan Provincial People's Hospital, Zhengzhou, 450003, China. .

Abstract:  Nicotinamide N-methyltransferase (NNMT) is an important methyltransferase involved in the biotransformation of many drugs and exogenous compounds. Abnormal expression of NNMT protein is closely associated with the onset and progression of many malignancies, but little is known about its role in esophageal squamous cell carcinoma (ESCC). Therefore, we aimed to explore whether NNMT plays any roles in carcinogenesis and metastasis in ESCC. NNMT expression was determined by immunohistochemistry in ESCC and corresponding adjacent normal tissues. Functional experiments were performed to elucidate the effects of NNMT knockdown on the proliferation, apoptosis, cell cycle, migration, and epithelial-mesenchymal transition (EMT) in EC9706 and TE1 cells. NNMT expression was significantly elevated in ESCC tissues compared with corresponding adjacent normal tissues. Moreover, a significant association emerged between NNMT expression and lymph node metastasis. SiRNA-mediated knockdown of NNMT in ESCC cells can significantly suppress cell viability and migration, induce cell cycle arrest, and promote cell apoptosis. In addition, NNMT downregulation led to the reversal of EMT, as reflected by upregulation of the intercellular adhesion molecule E-cadherin and downregulation of the mesenchymal markers N-cadherin and Vimentin. Further study found that NNMT knockdown suppressed the Wnt/β-catenin signaling pathway. Taken together, these findings indicate that NNMT is a critical regulator of EMT in ESCC and may be a potential therapeutic target for ESCC metastasis. 

Retracted: No

PubPeer comments:
 Some percentages reported in this paper are very similar to those in another paper by the same first author. That paper is: * Sleep Disorders and Insomnia: Effects on a Young Population - Faustin Armel Etindele Sosso - EC Psychology and Psychiatry 2.1 (2017): 26- 32. Received: December 19, 2016; Published: January 25, 2017 ( ECPP paper ). The ECPP paper has no DOI, but it also appears to share similarities with DOI: 10.21767 2172-0479.1000109 mentioned here: https: pubpeer.com publications 734E7DFA70C246665183F61E7DC3BD This paper,  JNN paper , is listed as Received Date: June 17, 2017; Accepted Date: June 22, 2017; Published Date: June 26, 2017. Hence, the ECPP paper appears to be older. The JNN paper shows results in a cohort of 100 subjects, while the ECPP paper describes a cohort of 600 subjects. Some remarkable similarities are noted between the percentages of the two papers. Despite being two very differently sized cohorts, the cohorts had remarkably identical percentages of cardiovascular disease (23%), neurologic disease (12%), family members with insomnia (64%) or Alzheimer (35%). They also had the exact same percentage of cardiovascular disease (8%), musculoskeletal disease (18%), medication for neurologic disease (15%). In addition, prevalence of depression in both cohorts was exactly 69%, while 16% in both cohorts had an anxiety. Even the average well-being score (19+ -0.8) and dependency score (17.45+ -0.58) were exactly the same in both cohorts. Could the first author please explain these remarkable similarities? Boxes of the same color focus attention to percentages that are identical between these two studies. ![file] , 
 #1 Dear Dr M Bik, as i explained previously, this was not the final form of the paper and when request an errata for this short communication perform during my Msc, nobody reply to my emails (itu2019s been 2 years). The publisher just want to publish something and they send many emails to solicit you. When you submit something, they donu2019t replied to all the request. This will be fix soon. And you may see that since this paper I did not work again with this publisher due to strange things noticed. I even did not receive an authorproof before this pdf was put online. , 
 Dear Dr. Sosso, thank you for responding. You replied to concerns in one of your other papers that you made a mistake in the number of study subjects. So are you saying that you also made a mistake in this particular paper? What should be the correct numbers then? I am sure this can be quickly resolved if you could disclose here what the original numbers should be. , 
 Dear Dr. M Bik, Many thanks for your concerns. 1- the JNN paper is well written like that, numbers are corrects 2-Regarding the EC Cronicon paper, the entire section should not be there. In fact, editor asked revisions for it that we submitted. i say we because we are 5 co-authors in this paper, and i am not the lead author as well as the corresponding author or the responsible of data analysis. i wrote the introduction only and i share the questionnaire MHPE i developed during my thesis. This EC Cronicon paper was the results of an internship supervised by Prof Mitsu Nakamura before he retired. 3-Again here, editor publisher are not willing to update the paper because the lead author and the lab director did not want to pay APC. When he solicited our submission, the managing editor said it is free but after acceptance he asked some handling fess or maintenance fees...obviously nobody want to pay and then editor is not updating since this time the paper. 4-i will force publisher to update it very soon to clarify all this. Please when sharing informations or hot stuff on some blog or twitter, it is important to verify what you are sharing to avoid damaging the reputation of individual or his research center university. you may write me in private or to the true corresponding author to ask this question. In my case, i am a medical doctor doing research very rarely because i am swamped in hospital and school. Also, my former lab has a part-time statistician who handle analysis because medical postgraduate students like me have other stuff to manage. i wish to clarify also something, my research program is not with animals or young adults. All these publications were related to my training during my postgraduate study. Currently, as a researcher, i am studying sleep disorders using an ecoepidemiology approach with people who have Parkinson Disease. I am also interest in the influence of socioeconomic inequalities on neuropsychiatric diseases. as you may see, all these publications you looking for were published several years ago and in specific conditions. I will appreciated if the next time you can write me directly in private to ask anything you want. i will reply as soon as possible, but due to my duties in hospital; it may takes 2-3 days to received an answer. regards , 
 In #4 Dr. Sosso, you write: u201di wrote the introduction onlyu201d Are you certain that this is consistent with generally accepted authorship practices? I was under the impression that authorship is commonly credited only to authors that made a material scientific contribution to the paper in question and lessor contributions are often credited with an acknowledgment. , 
 #5 even if i just wrote the introduction, i contribute in sharing the questionnaire to participant and i am the one who created this online questionnaire for my thesis. Thus, in my case In my case i deserves authorship. And as far as i know, the lead author and the supervisor decided how they applied authorship rules and this is true everywhere in the world in any field. , 
 Dear Dr. Sosso, In #4 you write  *In fact, editor asked revisions for it that we submitted. i say we because we are 5 co-authors in this paper, and i am not the lead author as well as the corresponding author or the responsible of data analysis.* Does that refer to this paper (JNN) or to the ECPP paper? This JNN paper has three authors, and the ECPP paper has a single author, which is you. Could you please clarify how there can be 5 (instead of 3) co-authors, and what their roles were? Also, in both cases, you *are* the corresponding author, according to the title pages. ![file] I would also like you to clarify the affiliation and role of your two co-authors, please. Both Nakamuras appear to have no publications other than a couple of papers published in not-PubMed indexed journals. Of particular note, all those papers predominantly list your papers in their citations, and their email addresses are not from their institute but are gmail addresses. For further details I refer to this PubPeer post: https: pubpeer.com publications 3EB597DAEBAF3782A9A66D6829731F Could you take away any doubt about the identity and affiliation of these co-authors? , 
 Dear Dr. Etindele Sosso, could you clarify the position and role of your two co-authors? The Nakamuras appear to have no publications other than a couple of papers published in not-PubMed indexed journals. Of particular note, all those papers predominantly list your papers in their citations, and their email addresses are not from their institute but are gmail addresses. For further details I refer to this PubPeer post: https: pubpeer.com publications 3EB597DAEBAF3782A9A66D6829731F Could you take away any doubt about the identity and affiliation of these co-authors? , 
 #7 I have no contact with them since two years. They approached me during a conference and they said they like my presentation and wish to work with me. I saw they have a google scholar and a researchgate profile, for me it was enough. Both told me they are independent researchers, one graduated in Japan and the second in Germany (or Switzerland?). i am not looking who is citing me, i am just happy to see my citations increase (like every scientist). Thank for alerting me on this. i am reading your post and its the first time i saw these journals and these communications. Like i said before, i am an anesthesiologist and research is not my main duty. That s why i like collaboration because its allow me to contribute during the small free time i have. i will now become more regarding with any potential co-authors. , 
 #8 Dear Dr M Bik, i was talking about the ECPP paper. ,