Cholangiocarcinoma (CCA) is a highly aggressive malignancy with extremely poor prognoses. Anatomically, CCA is further classified as three subtypes including intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA based on their origin in the biliary tree (1). pCCA is the most prevalent type of CCA accounting for about 50%–60% of the total CCA cases, while dCCA and iCCA accounted for 20%–30% and 10%, respectively (2). The motility and morbidity of CCA are increasing rapidly in the recent decades, but the treatment options have few progresses (3). China has the highest incidence of CCA worldwide, and whether Chinese CCA patients have special molecular features is still unknown. In general, the rate of radical surgical resection of CCA is quite low, and the treatment options of unresectable or advanced-stage CCA are an urgent need. CCAs usually have poor responses to the classical adjuvant therapies such as chemotherapy or radiotherapy. Till 2020, there emerged the first FDA-approved target drug of CCA, pemigtinib, which was used for CCA with FGFR2 fusion or mutation (4). Overall, the 5-year overall survival rate (OS) of CCA is very unsatisfactory, remaining approximately 30% after radical resection (5). More biomarkers of CCA should be investigated because biomarker discovery is the initiation to find new drug targets and new treatment therapy.

Protein phosphorylation is a key post-translational modification mainly regulated by serine/threonine phosphatase and tyrosine phosphatase. Protein tyrosine phosphatase (PTP) family participates in numerous processes such as signal transduction and cell proliferation, via dephosphorylating the phosphor-tyrosine of substrates (6). In humans, PTPs consist of 107 members and are divided into four main subgroups, which are type-I cysteine-based PTP (including classical PTPs and dual-specific phosphatase), type-II cysteine-based PTP, type-III cysteine-based phosphatases, and aspartic acid-based PTPs (7). These PTPs have different tissue specificities, substrates, and functions. Genetic and epigenetic alterations in the PTP genes can result in aberrant tyrosine phosphorylation, and consequently lead to diverse effects including an uncontrollable cell proliferation and tumorigenesis (8, 9). Interestingly, both the tumor suppressing role and oncogenic functions of PTPs have been showed in cancer, and the putative oncogenic or tumor suppressive functions of PTP are considered to rely on the cellular context.

Dual-specificity phosphatases (DUSPs) have a dephos-phorylating activity to both threonine/serine and tyrosine residues (10). There are 61 DUSPs out of the 107 PTP members, which have heterogeneous forms and functions, and are further classified based on the specific domains and sequence similarity. DUSP11, also known as PIR1 (phosphatase interacting with RNA and ribonucleoprotein 1), is a unique member of atypical DUSPs which could bind directly to RNA and possess RNA 5’-triphosphatase and diphosphatase activities (11, 12). DUSP11 converts the 5’ triphosphate of microRNA precursors to a 5’ monophosphate, and regulates cellular noncoding RNAs levels (12–14). In addition to a catalysis towards RNA, more evidence showed that DUSP11 could also dephosphorylate proteins. For example, DUSP11 could attenuate lipopolysaccharide-induced macrophage activation by targeting TGF-β-activated kinase 1 (15). DUSP11 was considered to participate in cancer progression by several previous studies (16, 17), but its functions and regulation mechanisms in cancer are still unclear to date. The tissue specificity and functions in tumor of DUSP11 have not been well studied.

In our study, we investigated the expression of DUSP11 in 174 cases of CCAs, including 74 iCCAs, 64 pCCAs, and 36 dCCAs. Moreover, we classified the patients into subsets with low and high expressions of DUSP11, and evaluated the clinicopathological factors in these subsets. With univariate and multivariate analyses, we assessed the correlation between DUSP11 and the OS rate in 74 iCCAs, 64 pCCAs, and 36 dCCAs.

Compared with other common cancer types such as gastric cancer or lung cancer, CCA is characterized by its low rate of radical resection because of the specificity of the hepatic portal (19, 20). The low rate of radical surgery increases the difficulty of specimen obtainment and establishment of a large cohort (20, 21), which is the basement of biomarker identification and new drug target. However, more prognostic biomarkers of CCA are an urgent need to select the high-risk patients and help formulate the precise treatment. Our study collected a total of 174 cases of CCAs, which was a relatively large CCA cohort. We demonstrated for the first time that DUSP11 was an independent prognostic biomarker in CCA, suggesting that a high expression of DUSP11 was a post-operational risk and detecting DUSP11 could guide the individual treatment for patients with CCA.

In the seventh edition of AJCC/UICC in 2007, pCCA and dCCA were separated from eCCA and regarded as distinct subtypes (22). iCCA, pCCA, and dCCA have different morbidities, clinical characteristics, treatment strategies, and prognosis, but whether they have different biological features is still controversial (23). In some occasions, iCCA and eCCA have the same biomarkers such as EGFR and HER2 (24, 25), but several biomarkers exhibited a different prognostic significance in iCCA and eCCA (21, 26). In this study, we demonstrated that DUSP11 expression was correlated with a poor prognosis in iCCA but not eCCA. This result further supported that iCCA and eCCA are two distinct cancer types, which have different biological factors and biomarkers.

In the era of high-throughput sequencing, numerous genetic alterations, such as the mutation, deletion, duplication, or translocation of PTP genes, are reported to be linked with diverse cancer phenotypes (27). The underlying mechanisms of the tumor suppressor or oncogenic role of PTPs in tumorigenesis or tumor progression are not fully understood. The loss or genetic alterations of several PTPs are shown to promote tumorigenesis, proliferation, and metastasis in in vitro and in vivo models, and these PTPs are generally considered to be tumor suppressors, including PTEN in prostate and breast cancer (28–30), SHP1 in leukemia and lymphomas (31, 32), PTPRF in colon, breast, and lung cancer (33, 34), and DUSP4 in breast, pancreas, and thyroid cancer (35–38). On the other hand, several tumor PTPs were identified as tumor suppressors because their genetic variations or loss facilitate tumorigenesis and tumor progression. For example, SHP2 was considered as an oncogene in breast cancer, leukemia, and gliomas (39–43), and PTP4A3 is an oncogene in breast, gastric, and colon cancer (44–46). The studies of DUSP11 in cancer are very few and the role of DUSP11 in tumor progression is nearly in vacancy. This is the first study reporting a definite role of DUSP11 as an oncogene because it is significantly associated with iCCA prognosis. Our results expand the understanding of the role of the DUSP family in cancer, and indicates DUSP11 as a potential drug target of CCA.

Although PTPs are attracting more and more attention as an onco-protein or a tumor suppressor, the improvement of PTP inhibitors as specific inhibitors or target drugs remains challenging. To obtain the specific small-molecule inhibitors are difficult because the catalytic domains of PTPs are very conserved. Till now, only a small proportion of PTPs have specific inhibitors, such as PTP1B, SHP2, and PTPN9 (47–50). However, the interacting proteins, substrates, and molecular catalytic mechanism of DUSP11 are poorly understood, and there is still no available inhibitor of DUSP11. More studies on the expression profile of DUSP11 in cancer would help improve the therapeutic use of its potential inhibitor. We showed the clinical relevance of DUSP11 in CCA and suggested that the inhibitor towards DUSP11 may be a potential therapeutic strategy to CCA.

In conclusion, we, for the first time, investigated the expression of DUSP11 in 174 cases of CCAs, including 74 iCCAs, 64 pCCAs, and 36 dCCAs, and evaluated the clinical significance of DUSP11 by assessing DUSP11 correlation between the clinicopathological factors and prognosis. As a result, we demonstrated that DUSP11 expression was associated with tumor infiltration and the OS rate in iCCA, but not in pCCA or dCCA. DUSP11 was an independent biomarker of iCCA, indicating a poor prognosis. Our results suggested that a high expression of DUSP11 was a post-operational risk factor, and detecting DUSP11 could guide the individual treatment for patients with CCA.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of Chinese Academy of Medical Sciences and Peking Union Medical College and National Cancer Center Shenzhen Hospital. The patients/participants provided their written informed consent to participate in this study.

Concept and design: XC. Administrative support: LX and PW. Specimen collection: XC, LX, PW, WZ, WL, and TL. Collection and assembly of data: XC, LX, PW, WZ, WL, and TL. Data analysis and interpretation: LX and PW. All authors contributed to the article and approved the submitted version.

The study is supported by Sanming Project of Medicine in Shenzhen (No. SZSM202011010) and Sanming Project of Medicine in Shenzhen (No. SZSM201911008).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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