Apparent HeLa cell line mixup earns a paper an expression of concern

A journal has issued an expression of concern for a 2011 paper after recognizing that the researchers may have been using contaminated cell lines. 

The article, “Downregulation of NIN/RPN12 binding protein inhibit [sic] the growth of human hepatocellular carcinoma cells,” appeared in Molecular Biology Reports, a Springer Nature title. In it, the authors, from China Medical University Shengjing Hospital, sought to find:

whether the suppression of Nob1 by short hairpin RNA (shRNA) inhibits the growth of human hepatocellular carcinoma (HCC) cells. Recombinant lentiviral shRNA expression vector carrying Nob1 was constructed and then infected into human HCC cell line SMMC-7721

Perhaps they did, and the paper has been cited 21 times, according to Clarivate Analytics’ Web of Science. However, experimental lines of SMMC-7721 cells are among the many cell lines known to have been contaminated by HeLa cells, named for Henrietta Lacks — highly proliferative cervical cancer cells that have overrun labs worldwide. So perhaps they didn’t. 

As the EoC states

The Editor-in-Chief would like to alert readers that this article [1] includes a problematic cell line. After further analysis, SMMC-7721 is shown to be a HeLa derivative ( Because of this, readers are asked to interpret the results with caution.

None of the authors have responded to any correspondence from the editor about this editorial expression of concern.

We wondered why the article was subject to an EoC rather than retraction. Jonathan Brody, the editor-in-chief of the journal, told us that without further testing, it’s not clear whether the cells in the paper were in fact HeLa derivatives:

In at least three different laboratories in Asia and Europe SMMC7721 cell lines were identified as HeLa cells but that does not mean that the cells used in the article published by MOLE in 2011 are HeLa cells – We would need to have the authors test these cells in order to make such conclusions therefore we published an expression of concern.

Amanda Capes-Davis, the Founding Manager and Honorary Scientist at CellBank Australia, and the chair of the International Cell Line Authentication Committee (ICLAC), said: 

this paper highlights the challenges of correcting the record when it comes to misidentified cell lines. The first publication to point out a problem with SMMC-7721 dates back to 2015 (DOI: 10.1096/fj.14-266718), which was three years after the paper that gave rise to the Expression of Concern here. I admire the editors for acting on this 2012 paper, but hope they will consider taking it further to a full retraction.

Capes-Davis added that: 

The challenge with many of these Chinese cell lines is that they were established in the 1970s or 1980s, and then passed from lab to lab.  Testing was difficult to access so problem cell lines were widely shared without anyone realizing.  We have colleagues in China who have tried to look for early samples, but often by the time they did this, the original investigators had retired and their labs closed down. … 

Realistically, it’s highly likely that when at least three different labs have tested and found that the cell line is HeLa, the same will be true for other studies.

Capes-Davis said she has seen recent improvement in the awareness of the cell line scramble:  

ICLAC urges that labs authenticate their cell lines before they start to work with them, using a genotype-based method such as STR profiling, and that information is slowly entering the mainstream thanks to the efforts of many stakeholders (including journals and funding bodies such as NIH). Information about misidentified cell lines is also more widely available compared to a few years ago, thanks to the ICLAC Register of Misidentified Cell Lines and the vast body of knowledge that is made available through Cellosaurus.

Past manuscripts remain an ongoing challenge, due to their widespread use of misidentified cell lines and ambiguous cell line names.  A name such as SMMC-7721 is fairly easy to flag, but other names such as “Chang liver” are not!  However, there are some very encouraging initiatives such as the increasing use of RRIDs (unique identifiers that reduce naming problems) and the development of automated searches that can be used to screen and flag problematic cell line information.

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