Unique expression features of cancer‐type organic anion transporting polypeptide 1B3 mRNA expression in human colon and lung cancers

Abstract

Background We have previously identified the cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3) mRNA in several human colon and lung cancer tissues. Ct-OATP1B3 is a variant of the liver-type OATP1B3 (Lt-OATP1B3) mRNA, which is a hepatocyte plasma membrane transporter with broad substrate specificity. However, in cancer tissues, both the detailed characteristics of Ct-OATP1B3 mRNA expression and its biological functions remain unclear. With this point in mind, we sought to characterize Ct-OATP1B3 mRNA expression in colon and lung cancer tissues. In addition, we attempted to obtain functional implication of Ct-OATP1B3 in cancer cells. Methods Matched pairs of cancer and normal tissues were collected from 39 colon cancer and 28 lung cancer patients. The OATP1B3 mRNA expression levels in each of these tissues were separately determined by quantitative real-time polymerase chain reaction. Mann–Whitney U test and Fisher’s exact test were used in statistical analysis. The Ct-OATP1B3 functional expression in colon cancer cells was then examined by Western blotting and transport analyses. Results Ct-OATP1B3 mRNA, but not Lt-OATP1B3 mRNA, was abundantly expressed in colon cancer tissues at a higher detection frequency (87.2%) than that of the adjacent normal tissues (2.6%). Furthermore, it was found that Ct-OATP1B3 mRNA expression was often detected in early colon cancer stages (88.9%, n = 18), and that its expression was associated with well-differentiated colon cancer statuses. On the other hand, Ct-OATP1B3 mRNA also showed a predominant and cancer-associated expression profile in lung tissues, although at frequencies and expression levels that were lower than those obtained from colon cancer. As for attempts to clarify the Ct-OATP1B3 functions, neither protein expression nor transport activity could be observed in any of the cell lines examined. Conclusions Based on the unique characteristics of the Ct-OATP1B3 mRNA expression profile identified in this study, Ct-OATP1B3 mRNA can be expected to become a biomarker candidate for use in colon (and lung) cancer diagnosis. Simultaneously, our results advance the possibility that Ct-OATP1B3 might play yet unidentified roles, in addition to transporter function, in cancer cell biology.

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology

“…While OATP1B3 is predominantly expressed in liver under normal conditions, it has been detected in various malignant tissues including tumors of the cervix, intestines, liver, lung, pancreas, and genitourinary tract (Lancaster et al, 2013). A cancer-specific form of OATP1B3, also referred to as cancertype OATP1B3, has been identified in which an alternative splice site is used, resulting in a protein that is structurally different from that found in normal liver; the cancer-specific OATP1B3 transcript has been detected in malignant tissues from the colon (Nagai et al, 2012;Han et al, 2013;Thakkar et al, 2013;Sun et al, 2014), pancreas (Han et al, 2013;Thakkar et al, 2013), and lung (Nagai et al, 2012;Sun et al, 2014). Some commonly used detection methods for wild-type OATP1B3 do not detect this cancer-specific OATP1B3; therefore, studies that do not show expression of OATP1B3 in cancerous tissues must be interpreted with caution if they did not search for the cancer-specific variant (Evangeli et al, 2017).…”

“…Some commonly used detection methods for wild-type OATP1B3 do not detect this cancer-specific OATP1B3; therefore, studies that do not show expression of OATP1B3 in cancerous tissues must be interpreted with caution if they did not search for the cancer-specific variant (Evangeli et al, 2017). The transport function of the cancer-specific OATP1B3 variant for at least some substrates is significantly decreased or abolished (Thakkar et al, 2013;Sun et al, 2014), although transport of other substrates is similar to that of the wild-type transporter (Imai et al, 2013).…”

Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions

“…For OATP1B1 expression in hepatocellular carcinoma, some studies reported increased expression while one reported unchanged compared to control [ 104 , 105 , 106 ]. Recently, a cancer-type OATP1B3 mRNA was identified in cancer cell lines and tissues from lung, colon and pancreatic origin [ 107 , 108 , 109 ]. Compared to wild-type OATP1B3 that is highly expressed in the liver, the cancer-type OATP1B3 lacks an N-terminus encoding region.…”

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

“…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 ).…”