Tumor Suppressor Gene Blocks Growth of Colon Cancer by Suppressing Key Tumor-Promoting Signaling Proteins

Cancer researchers have amassed a substantial body of evidence that points to the NLRX1 gene and its nlrx1 protein product as being powerful tumor suppressors that block the growth of colorectal cancer.

Investigators at the University of North Carolina (Chapel Hill, USA) reported in the March 10, 2016, online edition of the journal Cell Reports that nlrx1 served as a tumor suppressor in colitis-associated cancer (CAC) and sporadic colon cancer by keeping key tumor promoting pathways in check.

The investigators had found that mice lacking the NLRX1 gene were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor kappaB (NF-kappaB), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and interleukin 6 (IL-6).

Further studies of nlrx1 function were carried out in the mouse ApcMin/+ genetic model of sporadic gastrointestinal cancer. The ApcMin/+ mouse model has a point mutation in the Apc (adenomatous polyposis coli) gene, which predisposes the mice to increased spontaneous intestinal polyps. The current study revealed that compared to ApcMin/+ controls, ApcMin/+ mice lacking NLRX1 had a dramatically increased tumor burden accompanied by increased IL-6, STAT3, beta-catenin, and cathepsin B activation. Treatment of NLRX1−/−ApcMin/+ mice with anti-IL6R (interleukin 6 receptor) therapy reduced STAT3 activation, decreased tumor number, and increased survival, indicating that increased IL-6 was a causative factor in tumorigenesis linked to NLRX1-deficiency.

A drug already approved as a treatment for some inflammatory conditions, which blocks the IL-6 signaling protein, decreased tumor growth and activation of downstream cancer-causing signals in NLRX1 mice.

In addition to the results obtained in studies conducted with various mouse models, analysis of human colon cancer samples revealed that NLRX1 was expressed at lower levels than found in healthy controls in multiple patient cohorts. These findings indicated that the loss or reduction of NLRX1 may contribute to human colon cancers.

"What we are proposing is, if you can profile people with low NLRX1 in their colorectal cancer, you could consider using this therapy that we identified," said senior author Dr. Jenny P. Ting, professor of microbiology and immunology at the University of North Carolina. "We have identified a critical biomarker for this disease."

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