After last weeks big picture, strategic look at the state of cancer research, I thought it would be a nice idea to go the other extreme and look at some promising work that is happening at the cellular level.
microRNA is becoming an increasingly hot topic in oncology. Technically, they are are post-transcriptional regulators that bind to complementary sequences in messenger RNA. I tend to think of them more simply as gene regulators otherwise my brain starts to fry round the edges a bit.
Recently, He et al., (2005) demonstrated that when mice were altered to produce more Myc protein, miRNA was involved in the development of cancer. Mutated Myc has been implicated in several cancers. They engineered the mice to produce a surplus of types of miRNA found in lymphoma, ie mir-17-92 polycistron, and noticed that enforced expression of the mir-17-92 cluster acted with c-myc expression to accelerate tumour development. This miRNA cluster may therefore act as an oncogene and represent a valid therapeutic target in lymphoma.
Several miRNA’s have now been implicated in cancer. You will often see them numbered, eg miR-7, for ease of recognition. Last week, I came across another interesting article on miRNA and lung cancer. We know that EGFR plays a key role in the growth of epithelial cells, and faults in the network via over expression or mutation can lead to signalling overdrive and eventually lung cancer. One of the big questions is how do miRNAs mediate EGFR signalling to modulate tumorigenesis?
Chou et al., (2010) took a different approach from He et al. They looked at the interplay between EGFR, miRNA and Myc in lung cancer:
“To search for miRNAs regulated by EGFR, we performed miRNA microarray analysis of EGFR-silenced CL1-5 cells, a lung cancer cell line that overexpresses EGFR. Strikingly, we found that miR-7 is highly induced by EGFR in lung cancer. In the present study, we show for the first time that deregulated EGFR signaling induces miR-7, which in turn suppresses ERF and plays an important role in the oncogenesis of lung cancer cells.”
miRNA in the form of miR-7 is interesting, because it was previously found to regulate cell growth and apoptosis of cervical cancer and neuroblastoma cells. In this study, miR-7 was found to be overexpressed in human lung cancers and negatively correlated with disease free survival, echoing an important role of miR-7 in cancer progression.
One conundrum that can cause confusion is the finding that EGFR overexpression or amplification occurs more frequently in squamous cell carcinoma than in adenocarcinoma, but EGFR mutation occurs mostly in adenocarcinoma see Dacic et al., (2006). Chou et al., found that the level of miR-7 correlated with EGFR expression in squamous cell carcinoma and EGFR mutated adenocarcinoma, supporting the idea that deregulated EGFR signaling induces miR-7 expression.
In addition, miR-7 has been shown to suppress EGFR expression and function as a tumour suppressor in glioblastoma, but several reports have also shown that miR-7 expression correlates with poorer prognosis in patients with breast cancer and urothelial carcinoma. It is not impossible that miR-7 may therefore play different roles in different cancer types.
Another observation that caught my eye was:
“We have found that blocking the EGFR-mediated phosphoinositide 3-kinase (PI3K)/AKT pathway with LY294002 inhibitor also attenuates miR-7 expression, suggesting that the PI3K/AKT pathway participates in miR-7 regulation.”
There has been a recent flurry of interest in the roles of PI3K, AKT and MEK inhibition, especially in lung cancer, behind the research scenes. There are now more PI3K inhibitors in development than I can remember, but the key thing will be understanding the biology and translating it to well designed studies, otherwise we will be back to the sad old flawed model of combine it with standard chemo and then suck it and see. That sledgehammer to crush a grape approach is unlikely to work here, so we may see quite a few failures before someone cracks the code and designs some really smart studies.
I do think this is a very interesting pathway (as you can see from the many posts on the topic in the archives such as this one) and one that we may well see more results from the clinic in the future, once the research points to a clearer path for more logical combinations. Being first into the clinic doesn’t necessarily mean it’s the right approach. Sometimes, sitting back and working out the best approach first may lead to better results in the long run.
Finally, in the discussion, Chou et al., noted:
“In this study, we have shown that EGFR stimulated miR-7 expression via the Ras/ERK/Myc pathway to promote cell proliferation, anchorage-independent cell growth, and tumor formation of lung cancer cells.”
It will be fascinating to see if miR-7 emerges as a new prognostic biomarker and helps to provide a new valid therapeutic target in lung cancer. If you are interested in this field of research, do check out the links to the references below.
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, & Hammond SM (2005). A microRNA polycistron as a potential human oncogene. Nature, 435 (7043), 828-33 PMID: 15944707
Dacic S, Flanagan M, Cieply K, Ramalingam S, Luketich J, Belani C, & Yousem SA (2006). Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma. American Journal of Clinical Pathology, 125 (6), 860-5 PMID: 16690485
Chou, Y., Lin, H., Lien, Y., Wang, Y., Hong, C., Kao, Y., Lin, S., Chang, Y., Lin, S., Chen, S., Chen, H., Yeh, S., & Wu, C. (2010). EGFR Promotes Lung Tumorigenesis by Activating miR-7 through a Ras/ERK/Myc Pathway That Targets the Ets2 Transcriptional Repressor ERF Cancer Research, 70 (21), 8822-8831 DOI: 10.1158/0008-5472.CAN-10-0638