Exogenous IL‐6 induces mRNA splice variant MBD2_v2 to promote stemness in TP53 wild‐type, African American PCa cells

Teslow, Emily A.; Bao, Bin; Dyson, Greg; Legendre, Christophe; Mitrea, Cristina; Sakr, Wael; Carpten, John D.; Powell, Isaac J.; Bollig‐Fischer, Aliccia

doi:10.1002/1878-0261.12316

Cited by 18 publications

(25 citation statements)

References 53 publications

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“…Based on a review of the literature, we have generated the earliest reports on the role of epigenetic reader and alternative mRNA splicing variant MBD2_v2 to sustain and promote the tumor‐initiating CSC phenotype, first based on studies conducted in vitro (Bao et al ., ; Teslow et al ., ), and now based on in vivo experiments that link it to obesity. The results herein also elucidate that splicing factor SRSF2 is necessary for expression of MBD2_v2 in TNBC cells and for CSC survival.…”

Section: Discussionmentioning

confidence: 99%

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Obesity‐induced MBD2_v2 expression promotes tumor‐initiating triple‐negative breast cancer stem cells

et al. 2019

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Obesity is a risk factor for triple‐negative breast cancer ( TNBC ) incidence and poor outcomes, but the underlying molecular biology remains unknown. We previously identified in TNBC cell cultures that expression of epigenetic reader methyl‐CpG‐binding domain protein 2 ( MBD 2), specifically the alternative mRNA splicing variant MBD variant 2 ( MBD 2_v2), is dependent on reactive oxygen species ( ROS ) and is crucial for maintenance and expansion of cancer stem cell‐like cells ( CSC s). Because obesity is coupled with inflammation and ROS , we hypothesized that obesity can fuel an increase in MBD 2_v2 expression to promote the tumor‐initiating CSC phenotype in TNBC cells in vivo . Analysis of TNBC patient datasets revealed associations between high tumor MBD 2_v2 expression and high relapse rates and high body mass index ( BMI ). Stable gene knockdown/overexpression methods were applied to TNBC cell lines to elucidate that MBD 2_v2 expression is governed by ROS ‐dependent expression of serine‐ and arginine‐rich splicing factor 2 ( SRSF 2). We employed a diet‐induced obesity ( DIO ) mouse model that mimics human obesity to investigate whether obesity causes increased MBD 2_v2 expression and increased tumor initiation capacity in inoculated TNBC cell lines. MBD 2_v2 and SRSF 2 levels were increased in TNBC cell line‐derived tumors that formed more frequently in DIO mice relative to tumors in lean control mice. Stable MBD 2_v2 overexpression increased the CSC fraction in culture and increased TNBC cell line tumor initiation capacity in vivo . SRSF 2 knockdown resulted in decreased MBD 2_v2 expression, decreased CSC s in TNBC cell cultures, and hindered tumor formation in vivo . This report describes evidence to support the conclusion that MBD 2_v2 expression is induced by obesity and drives TNBC cell tumorigenicity, and thus provides molecular insights into support of the epidemiological evidence that obesity is a risk factor for TNBC . The majority of TNBC patients are obese and rising obesity rates threaten to further increase the burden of obesity‐linked cancers, which reinforces the relevance of this report.

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Section: Discussionmentioning

confidence: 99%

“…Real-time, semiquantitative RT-PCR analysis was performed as previously described (Bao et al, 2017;Teslow et al, 2018). RNA was harvested from pulverized snap-frozen tumors surgically excised from euthanized mice or from cultured cell lines using the RNeasy kit from Qiagen (Valencia, CA, USA).…”

Section: Semiquantitative Rt-pcr and Immunoblot Analysismentioning

confidence: 99%

Obesity‐induced MBD2_v2 expression promotes tumor‐initiating triple‐negative breast cancer stem cells

et al. 2019

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“…Less forthcoming has been functionally validated examples of AA-specific/enriched splice variants and corresponding protein isoforms that promote prostate cancer aggressiveness. A handful of examples have been described in the literature, including a resistance phenotype exhibited by PIK3CD-S to SMIs (8), hnRNPH1-mediated regulation of the AR-V7 isoform (9), and promotion of stemness in AA prostate cancer cell lines by the MBD2_v2 isoform (10). We now add FGFR3 to this growing list of functionally validated AA-specific/ enriched splice variants participating in enhanced oncogenicity.…”

Section: Discussionmentioning

confidence: 99%

“…While AS has been shown to play a role in prostate cancer development and progression, a link between AS and prostate cancer health disparities has been largely unexplored (but see refs. [8][9][10]. We recently uncovered global differential AS (dAS) events involving 2,520 distinct genes in a comparison between AA and EA prostate cancer specimens (8).…”

Section: Introductionmentioning

confidence: 99%

A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

Olender

Wang

Ching

et al. 2019

Molecular Cancer Research

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Alternative splicing (AS) has been shown to participate in prostate cancer development and progression; however, a link between AS and prostate cancer health disparities has been largely unexplored. Here we report on the cloning of a novel splice variant of FGFR3 that is preferentially expressed in African American (AA) prostate cancer. This novel variant (FGFR3-S) omits exon 14, comprising 123 nucleotides that encode the activation loop in the intracellular split kinase domain. Ectopic overexpression of FGFR3-S in European American (EA) prostate cancer cell lines (PC-3 and LNCaP) led to enhanced receptor autophosphorylation and increased activation of the downstream signaling effectors AKT, STAT3, and ribosomal S6 compared with FGFR3-L (retains exon 14). The increased oncogenic signaling imparted by FGFR3-S was associated with a substantial gain in proliferative and antiapoptotic activities, as well as a modest but significant gain in cell motility. Moreover, the FGFR3-S-conferred proliferative and motility gains were highly resistant to the pan-FGFR smallmolecule inhibitor dovitinib and the antiapoptotic gain was insensitive to the cytotoxic drug docetaxel, which stands in marked contrast with dovitinib-and docetaxel-sensitive FGFR3-L. In an in vivo xenograft model, mice injected with PC-3 cells overexpressing FGFR3-S exhibited significantly increased tumor growth and resistance to dovitinib treatment compared with cells overexpressing FGFR3-L. In agreement with our in vitro and in vivo findings, a high FGFR3-S/FGFR3-L expression ratio in prostate cancer specimens was associated with poor patient prognosis. Implications: This work identifies a novel FGFR3 splice variant and supports the hypothesis that differential AS participates in prostate cancer health disparities.

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“…Although impactful mutations altering gene expression, cell function, or cell viability have been observed, there is significant variability in reproducibility among varying cell lines (10,11). A portion of this variability is attributable to differences in genetic background (e.g., varying polymorphisms, epigenetic signatures, and gene expression patterns) among cell lines of the same ethnicity as well as between cell lines representing different ethnicities (12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Genetic Ancestry Analysis Reveals Misclassification of Commonly Used Cancer Cell Lines

Hooker

Woods-Burnham

Bathina

et al. 2019

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Given the scarcity of cell lines from underrepresented populations, it is imperative that genetic ancestry for these cell lines is characterized. Consequences of cell line mischaracterization include squandered resources and publication retractions. Methods: We calculated genetic ancestry proportions for 15 cell lines to assess the accuracy of previous race/ethnicity classification and determine previously unknown estimates. DNA was extracted from cell lines and genotyped for ancestry informative markers representing West African (WA), Native American (NA), and European (EUR) ancestry. Results: Of the cell lines tested, all previously classified as White/Caucasian were accurately described with mean EUR ancestry proportions of 97%. Cell lines previously classified as Black/African American were not always accurately described. For instance, the 22Rv1 prostate cancer cell line was recently found to carry mixed genetic ancestry using a much smaller panel of markers. However, our more comprehensive analysis determined the 22Rv1 cell line carries 99% EUR ancestry. Most notably, the E006AA-hT prostate cancer cell line, classified as African American, was found to carry 92% EUR ancestry. We also determined the MDA-MB-468 breast cancer cell line carries 23% NA ancestry, suggesting possible Afro-Hispanic/ Latina ancestry. Conclusions: Our results suggest predominantly EUR ancestry for the White/Caucasian-designated cell lines, yet high variance in ancestry for the Black/African Americandesignated cell lines. In addition, we revealed an extreme misclassification of the E006AA-hT cell line. Impact: Genetic ancestry estimates offer more sophisticated characterization leading to better contextualization of findings. Ancestry estimates should be provided for all cell lines to avoid erroneous conclusions in disparities literature.

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Exogenous IL‐6 induces mRNA splice variant MBD2_v2 to promote stemness in TP53 wild‐type, African American PCa cells

Cited by 18 publications

References 53 publications

Obesity‐induced MBD2_v2 expression promotes tumor‐initiating triple‐negative breast cancer stem cells

Obesity‐induced MBD2_v2 expression promotes tumor‐initiating triple‐negative breast cancer stem cells

A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

Genetic Ancestry Analysis Reveals Misclassification of Commonly Used Cancer Cell Lines

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