New research published in Molecular Oncology may help explain why African American men are at a higher risk of being diagnosed with prostate cancer and a higher risk of dying from the disease compared with European American men.
When investigators analyzed prostate cancer samples from patients, they found that a signaling molecule called interleukin-6 (IL6) is overexpressed in tumor-adjacent tissues in African-American men compared with European-American men.
Additional experiments revealed that IL6 inhibits expression of the p53 tumor suppressor protein, promotes self-renewal of cancer cells, and is associated with stem cell-like properties in prostate cancer cell lines.
“Our most recent research into the biological underpinnings for why African American men are more likely to be diagnosed with prostate cancer and die of the disease relative to other races or ethnicities has uncovered that IL6 is enriched in the tissue environment surrounding high-grade prostate cancer tumors from African American men,” said senior author Dr. Aliccia Bollig-Fischer, of the Barbara Ann Karmanos Cancer Institute in Detroit. “Not only did we uncover evidence that IL6 inactivates the p53 tumor suppressor in this context, our research also revealed that IL6 from the cancer cell environment causes an increase of a protein variant called MBD2_v2. This fuels an expansion of aggressive cancer cells, known as prostate cancer stem cells, which are considered to be the source of therapy resistance and metastatic tumor growth.”
In a follow-up study underway, Dr. Bollig-Fischer’s laboratory team will gain a more complete understanding of this novel cancer cell signaling process activated by IL6 derived from the tumor environment. “Our goal is to identify opportunities to develop transformative, targeted therapies to overcome race disparities and improve outcomes for all men with aggressive prostate cancer,” she said.
Exogenous IL6 induces mRNA splice variant MBD2_v2 to promote stemness in TP53 wild-type, African American PCa cells.
Abstract
African American men (AAM) are at higher risk of being diagnosed with prostate cancer (PCa) and are at higher risk of dying from the disease compared to European American men (EAM).We sought to better understand PCa molecular diversity that may be underlying these disparities. We performed RNA-sequencing analysis on high-grade PCa to identify genes showing differential tumor versus noncancer adjacent tissue expression patterns unique to AAM or EAM. We observed that interleukin-6 (IL6) was upregulated in the nonmalignant adjacent tissue in AAM, but in EAM IL6 expression was higher in PCa tissue. Enrichment analysis identified that genes linked to the function of TP53 were overrepresented and downregulated in PCa tissue from AAM. These RNA-sequencing results informed our subsequent investigation of a diverse PCa cell line panel.We observed that PCa cell lines that are TP53 wild-type, which includes cell lines derived from AAM (MDA-PCa-2b and RC77T), did not express detectable IL6 mRNA. IL6 treatment of these cells downregulated wild-type TP53 protein and induced mRNA and protein expression of the epigenetic reader methyl CpG binding domain protein 2 (MBD2), specifically the alternative mRNA splicing variant MBD2_v2. Further investigation validated that upregulation of this short isoform promotes self-renewal and expansion of PCa cancer stem-like cells. In conclusion, this report contributes to characterizing gene expression patterns in high-grade PCa and adjacent noncancer tissues from EAM and AAM. The results we describe here advance what is known about the biology associated with PCa race disparities and the molecular signaling of CSCs.
Exogenous IL6 induces mRNA splice variant MBD2_v2 to promote stemness in TP53 wild-type, African American PCa cells.
Abstract
African American men (AAM) are at higher risk of being diagnosed with prostate cancer (PCa) and are at higher risk of dying from the disease compared to European American men (EAM).We sought to better understand PCa molecular diversity that may be underlying these disparities. We performed RNA-sequencing analysis on high-grade PCa to identify genes showing differential tumor versus noncancer adjacent tissue expression patterns unique to AAM or EAM. We observed that interleukin-6 (IL6) was upregulated in the nonmalignant adjacent tissue in AAM, but in EAM IL6 expression was higher in PCa tissue. Enrichment analysis identified that genes linked to the function of TP53 were overrepresented and downregulated in PCa tissue from AAM. These RNA-sequencing results informed our subsequent investigation of a diverse PCa cell line panel.We observed that PCa cell lines that are TP53 wild-type, which includes cell lines derived from AAM (MDA-PCa-2b and RC77T), did not express detectable IL6 mRNA. IL6 treatment of these cells downregulated wild-type TP53 protein and induced mRNA and protein expression of the epigenetic reader methyl CpG binding domain protein 2 (MBD2), specifically the alternative mRNA splicing variant MBD2_v2. Further investigation validated that upregulation of this short isoform promotes self-renewal and expansion of PCa cancer stem-like cells. In conclusion, this report contributes to characterizing gene expression patterns in high-grade PCa and adjacent noncancer tissues from EAM and AAM. The results we describe here advance what is known about the biology associated with PCa race disparities and the molecular signaling of CSCs.