Insights from HuR biology point to potential improvement for second-line ovarian cancer therapy

Yu, Hongliang; Peng, Weidan; Furuuchi, Narumi; DuHadaway, James B.; Jimbo, Masaya; Pirritano, Andrea; Dunton, Charles J.; Daum, Gary S.; Leiby, Benjamin E.; Brody, Jonathan R.; Sawicki, Janet A.

doi:10.18632/oncotarget.7840

Cited by 9 publications

(6 citation statements)

References 32 publications

(33 reference statements)

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“…35 A study reported that RalA plays an important role in OC. 36 AHSG is also called as α-2 Heremans-Schmid glycoprotein, which could participate in signaling pathways associated with cancer. 37…”

Section: Discussionmentioning

confidence: 99%

Using a panel of multiple tumor‐associated antigens to enhance the autoantibody detection in the immunodiagnosis of ovarian cancer

Wang

Qin

et al. 2018

J of Cellular Biochemistry

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Background: Ovarian cancer (OC) is a major malignancy affecting a large population over the world, and a biomarker that holds diagnostic potential is of critical importance. Recently, autoantibodies have been indicated as biomarkers in multiple cancer research. The current study was designed to explore the practice of using autoantibodies in diagnostic settings by the enzyme-linked immunosorbent assay of sera with a panel of tumor-associated antigens (TAAs).Methods: A panel of 12 TAAs was selected to detect the corresponding autoantibodies in sera sampled from 132 OC patients as case group and 147 normal healthy individuals as the control group. The diagnostic potential of this panel was evaluated by conventional evaluation, receiver operating characteristic (ROC) curve analyses, and classification tree analysis.Results: When the cutoff values were set as mean ± 2 SD for normal healthy individuals, the positive rates of antibodies to any single TAA were less than 20% both in OC and in normal healthy individuals. In a parallel screening approach, a panel of nine TAAs (p53, C-myc, p90, p62, AHSG, 14-3-3zeta, RalA, Koc, and p16), obtained optimal diagnostic performance in OC with the sensitivity of 61.4% at the 85.0% specificity. In addition, when the nine TAAs were combined with CA125, the sensitivity and specificity were improved to 94.7% and 78.2%, respectively. The ROC curve analyses showed that only the area under the receiver operating characteristic curves (AUCs) of antibodies against C-myc, Koc, and RalA was beyond 0.6, which were 0.732, 0.668, and 0.665, respectively. The AUC of the combination was up to 0.914 (P < 0.05).Decision tree analysis showed that C-myc, HCC1.3, RalA, and CA125 held high potential in the detection of OC. The panel of nine TAAs also identified 78.8% of OC patients who had normal CA125 levels in their serum samples, indicating that elevated CA125 and anti-TAA antibodies appeared to be independent but supplementary biomarkers for diagnosing OC. Conclusions:In summary, the current study further supports that a customized TAA panel can serve as a promising and powerful tool for immunodiagnosis of OC and may be particularly useful in patients with normal CA125 levels.

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Section: Discussionmentioning

confidence: 99%

Using a panel of multiple tumor‐associated antigens to enhance the autoantibody detection in the immunodiagnosis of ovarian cancer

Wang

Qin

et al. 2018

J of Cellular Biochemistry

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“…Moreover, increased HuR expression and cytoplasmic localization in tumors correlate with poor disease prognosis and advanced tumor staging [ 12 , 48 – 51 ]. Thus, there are many data points from multiple laboratories over various tumor types that HuR is a strong candidate target in cancer [ 7 , 18 , 19 , 52 ]. In this study, MS444 is used here as a tool compound for proof-of-principle for pharmacological HuR inhibition, and that targeting HuR with MS-444 has anti-tumor activity as a monotherapy in multiple pre-clinical models for CRC.…”

Section: Discussionmentioning

confidence: 99%

Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis

et al. 2016

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Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality. Observed during CRC tumorigenesis is loss of post-transcriptional regulation of tumor-promoting genes such as COX-2, TNFα and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it post-transcriptionally regulates genes through its interaction with 3′UTR AU-rich elements (AREs). Here, we examine the therapeutic potential of targeting HuR using MS-444, a small molecule HuR inhibitor. Treatment of CRC cells with MS-444 resulted in growth inhibition and increased apoptotic gene expression, while similar treatment doses in non-transformed intestinal cells had no appreciable effects. Mechanistically, MS-444 disrupted HuR cytoplasmic trafficking and released ARE-mRNAs for localization to P-bodies, but did not affect total HuR expression levels. This resulted in MS-444-mediated inhibition of COX-2 and other ARE-mRNA expression levels. Importantly, MS-444 was well tolerated and inhibited xenograft CRC tumor growth through enhanced apoptosis and decreased angiogenesis upon intraperitoneal administration. In vivo treatment of MS-444 inhibited HuR cytoplasmic localization and decreased COX-2 expression in tumors. These findings provide evidence that therapeutic strategies to target HuR in CRC warrant further investigation in an effort to move this approach to the clinic.

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“…HuR-transfected and control cells were fractionated, and immunoprecipitates of cytoplasmic lysates were prepared. HuR-bound mRNAs versus IgG-bound control were detected and quantified by qRT-PCR, as previously described (1,3,57,58), using the following specific probes from Thermo Fisher Scientific: STAT1 (Mm01257286_m1), B2M (Mm00437762_m1), REG3g (Mm00441127_m1), COX-2 (Mm03294838_g1), CFD (Mm01143935_g1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Mm99999915_g1 and Hs02786624_g1), and HuR (ELAVL1; Mm00516011_m1 and Hs00171309_m1).…”

mentioning

confidence: 99%

Elevated HuR in Pancreas Promotes a Pancreatitis-Like Inflammatory Microenvironment That Facilitates Tumor Development

Peng

Furuuchi

Aslanukova

et al. 2018

Molecular and Cellular Biology

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Human antigen R (ELAVL1; HuR) is perhaps the best-characterized RNA-binding protein. Through its overexpression in various tumor types, HuR promotes posttranscriptional regulation of target genes in multiple core signaling pathways associated with tumor progression. The role of HuR overexpression in pancreatic tumorigenesis is unknown and led us to explore the consequences of HuR overexpression using a novel transgenic mouse model that has a >2-fold elevation of pancreatic HuR expression. Histologically, HuR-overexpressing pancreas displays a fibroinflammatory response and other pathological features characteristic of chronic pancreatitis. This pathology is reflected in changes in the pancreatic gene expression profile due, in part, to genes whose expression changes as a consequence of direct binding of their respective mRNAs to HuR. Older mice develop pancreatic steatosis and severe glucose intolerance. Elevated HuR cooperated with mutant K-ras to result in a 3.4-fold increase in pancreatic ductal adenocarcinoma (PDAC) incidence compared to PDAC presence in K-ras alone. These findings implicate HuR as a facilitator of pancreatic tumorigenesis, especially in the setting of inflammation, and a novel therapeutic target for pancreatitis treatment.

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Insights from HuR biology point to potential improvement for second-line ovarian cancer therapy

Cited by 9 publications

References 32 publications

Using a panel of multiple tumor‐associated antigens to enhance the autoantibody detection in the immunodiagnosis of ovarian cancer

Using a panel of multiple tumor‐associated antigens to enhance the autoantibody detection in the immunodiagnosis of ovarian cancer

Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis

Elevated HuR in Pancreas Promotes a Pancreatitis-Like Inflammatory Microenvironment That Facilitates Tumor Development

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