Mini RNA-7 is a Major Tumor Supressor that Blocks the Oncogenic EGFR-PAK1 Signaling

Mini RNA of 21-22 nucleotides (also called SiRNAs) are known to regulate
gene expression, which were first discovered in the nematode C. elegans,
just a decade ago by Craig Mello of University of Massachusetts and Andrew
Fire of Stanford University (2006 Nobel laureates).

In 2005 one of the nematode mini RNAs called Let-7 was found by Frank Slack's group at Yale University to be a suppressor of Let-60/RAS gene, suggesting that this mini RNA (or a related human counterpart) could work as a tumor suppressor in human RAS cancers such as pancreatic and colon cancers.

Cell. 2005 ;120: 635-47.
RAS is regulated by the let-7 microRNA family.

Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier
E, Reinert KL, Brown D, Slack FJ.

Department of Molecular, Cellular and Developmental Biology, Yale University,
P.O. Box 208103, New Haven, CT 06520, USA.

Interestingly, this year two groups in US, Ben Purow's group at University
of Virginia and Rakesh Kumar's group at MD Anderson Cancer Center, found
that one of mini RNAs called MIR-7 (or Micro RNA-7) suppresses the malignant
growth of cancer cells such as glioma by inhibiting the expression of at
least two oncogenes encoding EGF receptor (EGFR or ErbB1) and the kinase
PAK1. According to the latter's group, the expression of MIR-7 is under
the control of a homeobox transcription factor called HoxD10.

Thus, in principle,any drugs that can activate this homeobox protein might serve as anti-cancer therapeutics that block the oncogenic EGFR-RAS-AKT-PAK1 signaling pathways which are essential for the growth of more than 70% of all human cancers and NF (neurofibromatosis) tumors.

All-trans retinoic acid (RA) was reported to induce HoxD10 gene (Merril et
al, 2004). Is RA alone sufficient to activate MIR-7 gene, inactivating PAK1 gene?

MIR-7 GFP Fusion Gene for Anti-cancer Drug Screening

If the promoter region of MIR-7 gene is identified, we could express GFP
under the control of this promoter, and using the GFP as a reporter, we
could screen for anti-cancer drugs that activate this promoter in nematode
in vivo, or human glioma cells in vitro.

It is of great interest to note that human MIR-7 is expressed mainly in brain,
pancreas and thyroid (Lee et al, 2008), where abnormal activation of PAK1
causes lethal cancers.

Cancer Res. 2008 May 15; 68: 3566-72.

microRNA-7 inhibits the epidermal growth factor receptor and the Akt
pathway and is down-regulated in glioblastoma.

Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, Lee
J, Fine H, Chiocca EA, Lawler S, Purow B.

Division of Neuro-Oncology, Neurology Department, University of Virginia
Health System, Charlottesville, Virginia, USA.


Cancer Res. 2008 Oct 15; 68: 8195-200.

MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and
regulates its functions.

Reddy SD, Ohshiro K, Rayala SK, Kumar R.

Department of Molecular and Cellular Oncology, The University of Texas
MD Anderson Cancer Center, Baylor College of Medicine, Houston, Texas 77030,
USA.