Cancer-type organic anion transporting polypeptide 1B3 is a target for cancer suicide gene therapy using RNA trans -splicing technology

Sun, Yuchen; Hofbauer, Josefina Piñón; Harada, Manami; Wöss, Katharina; Koller, Ulrich; Morio, Hanae; Stierschneider, Anna; Kitamura, Kazuko; Hashimoto, Mari; Chiba, Kazuhiro; Akita, Hidetaka; Anzai, Naohiko; Reichelt, Julia; Bauer, Johann; Guttmann‐Gruber, Christina; Furihata, Tomomi

doi:10.1016/j.canlet.2018.06.032

Cited by 11 publications

(8 citation statements)

References 37 publications

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“…By using primers that discriminate between liver- and cancer-type variants, we were able to demonstrate that Ct-SLCO1B3 transcripts were significantly expressed in RDEB-SCC cell lines and patient tumor biopsies as compared with non-tumor RDEB or normal human keratinocyte cell lines, making this variant transcript a potential therapeutic target as well in this tumor entity. Using the same RTM44 as described by Sun et al [ 17 ], we demonstrate here the successful introduction of HSVtk into the coding sequence of Ct-SLCO1B3 in the presence of functional RTM44, and tumor cell killing in cell culture and as well as in a xenograft mouse model for RDEB-SCC following treatment with the prodrug GCV. This study highlights the translatability of a specially designed RTM molecule to different malignancies.…”

Section: Introductionmentioning

confidence: 63%

“…In the present study, we utilized RTM44, previously proven to target Ct-SLCO1B3 in a colorectal cancer model. The design and generation of RTM44 has been described in detail by Sun et al [ 17 ]. Briefly, RTM44 consists of a 225-bp BD complementary to intronic sequences immediately following exon 1 of the Ct-SLCO1B3 transcript.…”

Section: Resultsmentioning

confidence: 99%

“…In the case of SMaRT, this has been achieved by trans -splicing a suicide gene to a cancer-specific target, thereby enforcing its cell-restricted expression. This approach has successfully been used to deliver the suicide gene thymidine kinase from herpes simplex virus 1 (HSVtk) into cancer cells, rendering cells sensitive to treatment with the prodrug ganciclovir (GCV) [ 14 , 15 , 16 , 17 ]. In detail, the HSVtk enzyme catalyzes the phosphorylation of GCV into an active cytotoxin that causes cell death by terminating DNA replication [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans-Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer

Woess

Sun

Morio

et al. 2022

IJMS

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Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA trans-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy.

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Section: Introductionmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans-Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer

Woess

Sun

Morio

et al. 2022

IJMS

Self Cite

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“…Cancer-specific transcript mRNA is an excellent target for the development of cancer therapies and biomarkers. Previous work successfully utilized herpes simplex virus-1 thymidine kinase with trans-splicing towards ct-OATP1B3 to develop a cancer suicide gene therapy in vitro and in vivo [50]. However, the transportation capability of ct-OATP1B3 for ICG and Gd-EOB-DTPA and the correlations between ct-OATP1B3 and cancer prognosis are still unknown.…”

Section: Discussionmentioning

confidence: 99%

Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging

Lee

Hsiao

2021

IJMS

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Membrane proteins responsible for transporting magnetic resonance (MR) and fluorescent contrast agents are of particular importance because they are potential reporter proteins in noninvasive molecular imaging. Gadobenate dimeglumine (Gd-BOPTA), a liver-specific MR contrast agent, has been used globally for more than 10 years. However, the corresponding molecular transportation mechanism has not been validated. We previously reported that the organic anion transporting polypeptide (OATP) 1B3 has an uptake capability for both MR agents (Gd-EOB-DTPA) and indocyanine green (ICG), a clinically available near-infrared (NIR) fluorescent dye. This study further evaluated OATP1B1, another polypeptide of the OATP family, to determine its reporter capability. In the OATP1B1 transfected 293T transient expression model, both Gd-BOPTA and Gd-EOB-DTPA uptake were confirmed through 1.5 T MR imaging. In the constant OAPT1B1 and OATP1B3 expression model in the HT-1080 cell line, both HT-1080-OAPT1B1 and HT-1080-OATP1B3 were observed to ingest Gd-BOPTA and Gd-EOB-DTPA. Lastly, we validated the ICG uptake capability of both OATP1B1 and OATP1B3. OAPT1B3 exhibited a superior ICG uptake capability to that of OAPT1B1. We conclude that OATP1B1 is a potential reporter for dual MR and NIR fluorescent molecular imaging, especially in conjunction with Gd-BOPTA.

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“…Imai et al [35] showed that ct-OATP1B3 was strongly expressed in colorectal cancer, cholangiocarcinoma, and pancreatic cancer cells. Due to the remarkable cancer-specific expression profile of ct-OATP1B3 [27,29], it may represent a promising molecular target for cancer therapy using the herpes simplex virus 1 thymidine kinaseganciclovir suicide gene system [43]. Nevertheless, ct-OATP1B3 displays defective membrane trafficking and only modest transport activity compared to lt-OATP1B3.…”

Section: Discussionmentioning

confidence: 99%

Low expression of organic anion-transporting polypeptide 1B3 predicts a poor prognosis in hepatocellular carcinoma

Chen

Jiang

et al. 2020

World J Surg Onc

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Objective: To detect the expression level of organic anion-transporting polypeptide 1B3 (OATP1B3) in hepatocellular carcinoma (HCC) and to determine the relationship between OATP1B3 expression, clinicopathological features, and prognosis. Methods: Immunohistochemical (IHC) staining was performed to detect the expression of OATP1B3 in 131 HCC specimens and in 89 adjacent nontumorous tissues. Moreover, the expression levels of OATP1B3 in 30 pairs of tumor and matched adjacent nontumorous tissues were detected by quantitative real-time polymerase chain reaction, and 34 pairs of tumor and matched adjacent nontumorous tissues were detected by Western blotting. The χ 2 test was applied to analyze the correlation between OATP1B3 expression and the clinical parameters of HCC patients. The prognostic value of OATP1B3 in HCC patients was estimated by Kaplan-Meier survival analysis and the Cox stepwise proportional hazards model. Results: Compared with that in adjacent nontumorous tissues (25.8%, 23/89), OATP1B3 expression was significantly downregulated in tumor tissues (59.5%, 78/131) (P < 0.0001). Moreover, OATP1B3 expression was markedly correlated with tumor size, recurrence, tumor differentiation, and tumor node metastasis (TNM) stage (P < 0.05 for each). However, age, sex, tumor capsule status, HBsAg, cirrhosis, tumor number, vascular invasion, and serum alpha fetoprotein were not associated with OATP1B3 expression. The overall survival (OS) and disease-free survival (DFS) of HCC patients who had high expression of OATP1B3 were significantly longer than those of patients with low expression (33.0% vs 12.9%, P = 0.001; 18.8% vs 5.3%, P < 0.0001). Cox multivariate analysis showed that OATP1B3, invasion, and TNM stage (P < 0.05 for each) were independent prognostic factors of OS in HCC patients and that OATP1B3 and TNM stage (both P < 0.05) were independent prognostic factors of DFS in HCC patients. Conclusions: The expression of OATP1B3 in HCC patients was significantly lower than that in adjacent nontumorous tissues. OATP1B3 expression may be a potential prognostic marker in HCC patients.

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Cancer-type organic anion transporting polypeptide 1B3 is a target for cancer suicide gene therapy using RNA trans -splicing technology

Cited by 11 publications

References 37 publications

Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans-Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer

Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans-Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer

Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging

Low expression of organic anion-transporting polypeptide 1B3 predicts a poor prognosis in hepatocellular carcinoma

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