Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

Choi, Soyoung; Wang, Dunrui; Chen, Xiang; Tang, Laura H.; Verma, Akanksha; Chen, Zhengming; Kim, Bu Jung; Selesner, Leigh; Robzyk, Kenneth; Zhang, George; Pang, Sharon; Han, Teng; Chan, Chang S.; Fahey, Thomas J.; Elemento, Olivier; Du, Yi‐Chieh Nancy

doi:10.1101/598334

Cited by 3 publications

(12 citation statements)

References 16 publications

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“…1D). We have reported that BON1 cells upregulate RHAMM, especially RHAMM B isoform, compared to normal human islets 18 . We incubated BON1_TGL_shLacZ and BON1_TGL_shRHAMM cells with Au/L/HA NPs for 12 h and then imaged the cells under fluorescence microscope.…”

Section: Rhamm B Is Crucial In Pnets and Mediates Cellular Uptake Of mentioning

confidence: 84%

“…To validate the critical role of human RHAMM B in metastatic progression of PNETs 18 , we generated a new batch of mouse PNET N134 cells expressing human RHAMM B . The expression of human RHAMM B (~82 kDa) was verified in the new N134-RHAMM B cell line by Western blotting using an antibody specific against human RHAMM (Fig.…”

Section: Rhamm B Is Crucial In Pnets and Mediates Cellular Uptake Of mentioning

confidence: 99%

“…1C). To further verify the RHAMM B -dependent HA-coated AuNPs uptake, we used a previously generated human PNET cell line with reduced level of RHAMM by shRNA knockdown (BON1_TGL_shRHAMM) and a control cell line, BON1_TGL_shLacZ 18 (Fig. 1D).…”

Section: Rhamm B Is Crucial In Pnets and Mediates Cellular Uptake Of mentioning

confidence: 99%

“…RHAMM B overexpressing cell line, N134-RHAMM B , was generated using RCASBP as described 39,40 . BON1_TGL_shLacZ and BON1_TGL_shRHAMM cells were generated in the previous study 18…”

Section: Cell Culture and Western Blot Analysismentioning

confidence: 99%

“…RHAMM has limited protein expression in adult human tissues, but it is upregulated in histologically high-grade tumors in general 17 . Several RHAMM alternative splicing isoforms have been identified, and we have previously found that RHAMM isoform B (RHAMM B ) was the predominant isoform upregulated in human PNETs and various cancers [17][18][19][20] . We hypothesized that RHAMM B -targeting delivery may target PNETs specifically with minimal adverse effects to other cells.…”

Section: Introductionmentioning

confidence: 99%

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RHAMM^B-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment

Chen

Lee

Song

et al. 2021

Preprint

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The incidence of pancreatic neuroendocrine tumor (PNET) has continued to rise. Due to their indolent feature, PNET patients often present with incurable, metastatic diseases. Novel therapies are urgently needed. We have previously shown that Receptor for Hyaluronic Acid-Mediated Motility isoform B (RHAMMB) and Bcl-xL are upregulated in PNETs and both of them promote PNET metastasis. Because RHAMM protein is undetectable in most adult tissues, we hypothesized that RHAMMB could be a gateway for nanomedicine delivery into PNETs. To test this, we developed RHAMMB-targeting nanoparticle. Inside this nanoparticle, we assembled siRNA against Bcl-xL (siBcl-xL) and mitochondria-fusing peptide KLA. We demonstratsed that RHAMMB-positive PNETs picked up the RHAMMB-targeting nanoparticles. siBcl-xL or KLA alone only killed 30% of PNET cells. In contrast, a synergistic killing effect was achieved with the co-delivery of siBcl-xL and KLA peptide in vitro. Unexpectedly, siBcl-xL induced cell death before reducing Bcl-xL protein levels. The systemically-injected RHAMMB-targeting nanoparticles carrying siBcl-xL and KLA peptide significantly reduced tumor burden in mice bearing RHAMMB-positive PNETs. Together, these findings indicate that the RHAMMB-targeting nanotherapy serves as a promising drug delivery system for PNET and possibly other malignancies upregulating RHAMMB. The combination of siBcl-xL and KLA peptide can be a therapy for PNET treatment.

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Section: Rhamm B Is Crucial In Pnets and Mediates Cellular Uptake Of mentioning

confidence: 84%

Section: Rhamm B Is Crucial In Pnets and Mediates Cellular Uptake Of mentioning

confidence: 99%

Section: Rhamm B Is Crucial In Pnets and Mediates Cellular Uptake Of mentioning

confidence: 99%

“…RHAMM B overexpressing cell line, N134-RHAMM B , was generated using RCASBP as described 39,40 . BON1_TGL_shLacZ and BON1_TGL_shRHAMM cells were generated in the previous study 18…”

Section: Cell Culture and Western Blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RHAMM^B-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment

Chen

Lee

Song

et al. 2021

Preprint

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High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer

Feng

Lin

Chen

et al. 2021

Preprint

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Pancreatic cancer has the lowest survival rate in all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages. A better therapeutic development for this devastating disease is urgently needed. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm-/- mice. However, we found that Rhamm-/- mice expressed a truncated HMMRΔexon8-16 protein at higher abundance levels than wild-type RHAMM. While HMMRΔexon8-16 did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRASG12D mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRASG12D mice with heterozygous p53 knockout. KrasG12D PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of HMMRΔexon8-16 was not apparent in these mice with short-life span. In addition, HMMRΔexon8-16 shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, high levels of HMMRΔexon8-16 that lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC) accelerated pancreatic cancer progression.

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Signature of gene aberrant alternative splicing events in pancreatic adenocarcinoma prognosis

Yao

Tang

et al. 2021

J. Cancer

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Alternative splicing (AS), as an effective and universal mechanism of transcriptional regulation, is involved in the development and progression of cancer. Therefore, systematic analysis of alternative splicing in pancreatic adenocarcinoma (PAAD) is warranted. The corresponding clinical information of the RNA-Seq data and PAAD cohort was downloaded from the TCGA data portal. Then, a java application, SpliceSeq, was used to evaluate the RNA splicing pattern and calculate the splicing percentage index (PSI). Differentially expressed AS events (DEAS) were identified based on PSI values between PAAD cancer samples and normal samples of adjacent tissues. Kaplan-Meier and Cox regression analyses were used to assess the association between DEAS and patient clinical characteristics. Unsupervised cluster analysis used to reveal four clusters with different survival patterns. At the same time, GEO and TCGA combined with GTEx to verify the differential expression of AS gene and splicing factor. After rigorous filtering, a total of 45,313 AS events were identified, 1,546 of which were differentially expressed AS events. Nineteen DEAS were found to be associated with OS with a five-year overall survival rate of 0.946. And the subtype clusters results indicate that there are differences in the nature of individual AS that affect clinical outcomes. Results also identified 15 splicing factors associated with the prognosis of PAAD. And the splicing factors ESRP1 and RBM5 played an important role in the PAAD-associated AS events. The PAAD-associated AS events, splicing networks, and clusters identified in this study are valuable for deciphering the underlying mechanisms of AS in PAAD and may facilitate the establishment of therapeutic goals for further validation.

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Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

Cited by 3 publications

References 16 publications

RHAMM^B-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment

RHAMM^B-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment

High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer

Signature of gene aberrant alternative splicing events in pancreatic adenocarcinoma prognosis

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Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

Cited by 3 publications

References 16 publications

RHAMMB-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment

RHAMMB-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment

High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer

Signature of gene aberrant alternative splicing events in pancreatic adenocarcinoma prognosis

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RHAMM^B-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment

RHAMM^B-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment