Characterization of Liver- and Cancer-type-Organic Anion Transporting Polypeptide (OATP) 1B3 Messenger RNA Expression in Normal and Cancerous Human Tissues

Abstract

Background Membrane transport protein organic anion transporting polypeptide (OATP) 1B3 mediates the cellular uptake of many drugs including anti-cancer drugs (e.g. paclitaxel). In addition to the well-recognized hepatic expression and function of OATP1B3 [herein named liver-type (Lt) OATP1B3], OATP1B3 also expresses in cancers and has been postulated to play a role in cancer therapy presumably by facilitating the influx of anti-cancer drugs. Recently, a cancer type (Ct)-OATP1B3 mRNA variant was identified in colon and lung cancer tissues, which encodes truncated Ct-OATP1B3 with negligible transport activity. Other than colon and lung cancers, reports on mRNA expression of OATP1B3 in other cancers cannot distinguish between the Lt- and Ct-OATP1B3. Objective The current studies were designed to characterize the expression of Lt- and Ct-OATP1B3 mRNA in ovarian, prostate, bladder, breast, and lung tissues. Methods Lt- and Ct-OATP1B3 isoform-specific PCR primers were utilized to determine the mRNA levels of Lt- and Ct-OATP1B3, respectively. An expression vector expressing green fluorescent protein (GFP)-tagged Lt-OATP1B3 was transiently transfected into the ovarian cancer cell line SKOV3. Confocal live-cell microscopy was utilized to determine the localization of GFP-Lt-OATP1B3 in SKOV3 cells. Results For the first time, Lt-OATP1B3 mRNA was detected in ovarian, prostate, bladder and breast cancers. The GFP-Lt-OATP1B3 expressed in the ovarian cancer cell line SKOV3 has a plasma membrane localization pattern as shown by confocal microscopy. Conclusion Our findings are supportive of the potential role of Lt-OATP1B3 in cancer therapy.

Clinical Significance of Organic Anion Transporting Polypeptide Gene Expression in High-Grade Serous Ovarian Cancer

“…Importantly, SLCO1B3 expression was only detected in 1/21 cysts (4.8%) and in 38.5% of HGSOC tissues (FDR = 0.0079). Although our analysis did not discriminate between lt- SLCO1B3 and the cancer-type variant, it is most likely that ct- SLCO1B3 might be the prominent isoform in the tumors investigated (Furihata et al, 2015 ; Thakkar et al, 2015 ; Alam et al, 2018 ). Both, SLCO4C1 (FDR = 3.1x10 −4 ) and SLCO6A1 (FDR = 0.14) were not detectable in any of the benign ovarian cysts, however, there was no significant difference between the broad range of SLCO6A1 expression in the 14.1% of HGSOC samples compared with the benign ovarian cysts.…”

“…Novel SLCO1B3 variants were identified in cancerous tissues. A cancer-type variant with a distinct 5′region, termed cancer-type (ct)- SLCO1B3 coding for the cancer-type (ct)-OATP1B3 transporter was identified as the main OATP1B3 variant in colon, lung (Sun et al, 2014 ) pancreatic (Thakkar et al, 2013 ), and also ovarian cancer (Alam et al, 2018 ).…”

“…From all established members of the OATP family, lt-OATP1B3 has been extensively characterized for its function as an uptake transporter for several established OATP substrates and for its role in paclitaxel uptake (van de Steeg et al, 2013 ). Because the OATP variant has poor transport capacity compared to the lt-OATP1B3, paclitaxel uptake by ct-OATP1B3 into ovarian cancer cells is unlikely (Thakkar et al, 2013 ; Sun et al, 2014 ; Furihata et al, 2015 ; Sissung et al, 2017 ; Alam et al, 2018 ).…”

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

“…Because of the low expression of OATP1B3 in HCC [9,26], it has received little attention from researchers in the past. Many recent studies have demonstrated that OATP1B3 is expressed in various cancer cells and/or tissues [8,27]. Moreover, OATP1B3 protein expression is highly correlated with the clinicopathological features of cancer patients and has prognostic value [15][16][17]28].…”

“…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.…”