Table 1 Summary of potential targets for platinum resistance in CCC

 Pre target

ABCC3

Function

ABCC3 is expressed in the liver, small intestine, and colon. ABCC3 belongs to the ABCC subfamily, consisting of 13 members in mammals that are divided into three classes: multi-drug resistance proteins, sulfonylurea receptors, and the cystic fibrosis transmembrane conductance regulator [15]. ABCC3 transports monovalent bile salts (i.e., taurocholate and glycocholate) and sulfated bile salts(i.e., taurochenodeoxycholate-3-sulfate, taurolithocholate-3-sulfate) [15]

In cancer tissues

Overexpression of ABCC3, which transports chemotherapeutic agents, has been associated with paclitaxel resistance in breast cancer cell lines [16, 17] and cisplatin resistance in ovarian cancer cell lines [18]

In CCC

One study reported that ABCC3 mRNA expression in CCC was significantly higher than that in SAC [19]. However, no study to date has investigated potential mechanisms of platinum resistance in CCC

Annexin A4

Function

Annexin A4 (Anx A4) is a member of the Ca²⁺-regulated and phospholipid-binding annexin protein superfamily, and is believed to be involved in exocytosis and regulation of epithelial Cl⁻ secretion [20]

In cancer tissues

Studies indicate that Anx A4 up-regulation promotes tumor progression and chemoresistance in colorectal cancer, esophageal squamous cell carcinoma, endometrial carcinoma, gastric cancer, chemoresistant lung cancer, malignant mesothelioma, renal cell carcinoma, ovarian clear cell carcinoma (CCC), cholangiocarcinoma, hepatocellular carcinoma, breast cancer, and laryngeal cancer [21]

In CCC

Enhanced Anx A4 expression was identified in both clinical samples and ovarian CCC cell lines by 2-D differential gel electrophoresis (2D-DIGE) and mass spectrometry [22]. Anx A4 confers chemoresistance to ovarian CCC cell lines [23]. Proposed mechanisms of annexin-A4-mediated chemoresistance include (1) reduction of intracellular platinum content and (2) enhancement of NF-kB transcriptional activity via interaction of Anx A4 with NF-kB. Anx A4 is one of the most investigated platinum resistance factors in CCC [20, 22–25]

Glutathione peroxidase 3 (GPx3)

Function

The Glutathione Peroxidase (GPx) family is composed of eight members (GPx1–GPx8) that play roles in removing redundant reactive oxygen species (ROS) to reduce oxidative damage to host cells. The GPx3 gene is located on chromosome 5q23 and encodes a protein that accounts for nearly all GPx activities in plasma [26]

In cancer tissues

GPx3 expression has been reported in hepatocellular carcinoma, gastric cancer, acute myeloid leukemia, and clear cell renal cell carcinoma [27]. One study reported a correlation between GPx3 methylation and chemoresistance in head and neck cancer (HNC), which may serve as a potential prognostic indicator of HNC after cisplatin-based chemotherapy [28]

In CCC

Only one study to date has investigated the role of GPx3 in CCC [29]. The GPx3 gene was found to be highly expressed in CCC by DNA microarray analysis. GPx3 suppression by RNA interference increased cisplatin sensitivity by approximately 4-fold in CCC cell lines. Since GPx3 suppression increased cisplatin sensitivity of CCC cells, GPx3 may be a candidate gene associated with platinum resistance in CCC [29]

 On target

ERCC1 (NER system)

Function

ERCC1 was the first human DNA repair gene identified by molecular cloning. The ERCC1 and ERCC4 genes encode the two subunits of ERCC1-XPF nuclease, an enzyme that plays an important role in DNA repair and maintenance of genomic stability [30]. ERCC1-XPF nuclease nicks DNA specifically at junctions between double-stranded and single-stranded DNA, when the single-strand is oriented in a 5′ to 3′ direction away from a junction. ERCC1-XPF is a core component of nucleotide excision repair and plays a role in interstrand crosslink repair, some pathways of double-strand break repair by homologous recombination and end-joining, as a backup enzyme in base excision repair, and in telomere length regulation [30]

In cancer tissues

ERCC1 is perhaps one of the most important components of the NER pathway and a key determinant of cisplatin resistance. When we consider the role that it plays in other DNA repair processes, such as recombination, it is observed that in recent years, ERCC1 has become one of the most studied prognostic factors of platinum therapy [31]. ERCC1 is reportedly a platinum-resistance factor in cancers of the ovary, lung, colorectum, and stomach [31–34]

In CCC

Although a detailed investigation was not conducted, one study detected higher ERCC1 mRNA levels in CCC specimens than other histological types of epithelial ovarian cancer [35]. Because ERCC1 was found to play an important role in platinum resistance in other cancers, further investigations into the role of ERCC1 in CCC are expected

 Post target

Galectin 3

Function:

The galectins comprise a family of 14 members of β-galactoside-binding proteins, which are characterized by an affinity for β-galactosides and a conserved sequence in the carbohydrate recognition domain that binds to the carbohydrate portion of cell surface glycoproteins or glycolipids [36]. Galectin 3 is widely expressed in epithelial and immune cells in the gastric mucosa, colon mucosa, mammary epithelium, and prostate epithelium, as well as monocytes and macrophages. The Galectin 3 gene encodes a 31-kDa multifunctional oncogenic protein that plays a role in the regulation of cell growth, adhesion, proliferation, and apoptosis, as well as angiogenesis [36]

In cancer tissues

Galectin 3 has been implicated in many aspects of cancer progression, such as tumor cell adhesion, proliferation, differentiation, and metastasis [37], and is associated with platinum resistance in cancers of the ovary, pancreas, and prostate [38–41]. Galectin 3 has also been shown to protect cells against chemotherapy-induced apoptosis and has been implicated in the regulation of universal apoptosis commitment [37]

In CCC

Only one study to date has investigated the role of Galectin 3 in CCC [42]. Cisplatin-induced apoptosis was increased after Galectin 3 knock-down. Immunohistochemical staining showed that Galectin 3 expression in CCC was significantly more frequent than in SAC. Because p27 protein expression was decreased after Galectin 3 knock-down, the author concluded that Galectin 3 expression in CCC might contribute to decreased cell proliferation and lead to cisplatin resistance [42]

 Off target

EGFR

Function

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that belongs to the receptor tyrosine kinase family of growth factor receptors and participates in important physiological process, such as cell survival, proliferation, and motility [43]

In cancer tissues

EGFR overexpression has been associated with advanced disease and poor survival of patients with cancers of the breast, lung, liver, prostate, and ovary [43]. Alterations to EGFR coding sequences are also frequently found in human cancers. Most variants with deletions in the extracellular domain are correlated with poor survival. In general these variants are constitutively active and confer a growth advantage and increased malignant potential to tumor cells [43, 44]. Overexpression or mutated EGFR is reportedly associated with platinum resistance in lung and ovarian cancer [14, 43, 45]

In CCC

A previous study reported EGFR overexpression in approximately 60 % CCC specimens and selective inhibition of the EGFR decreased growth and invasion of ovarian CCC cells [46]. Another study reported that EGFR inhibition increased cisplatin efficacy in ovarian CCC cells [47]. Together, the results of these studies suggest that EGFR is an important therapeutic target to improve platinum-resistance in CCC

HER2

Function

HER2 (ErbB2) is a type I transmembrane protein that belongs to the EGFR family, which includes EGFR, ErbB1, HER1, HER3, and −4 (ErbB3 and −4) [48]. Normal HER2 function is associated with cellular differentiation, growth, development, and apoptosis via activation of tyrosine kinase activity through dimerization of HER2, with itself or other members of the EGFR family [48]

In cancer tissues

Amplification or overexpression of HER2 occurs in approximately 15–30 % of breast cancers and 10–30 % of gastric/gastroesophageal cancers, and serves as a prognostic and predictive biomarker. HER2 overexpression has also been identified in cancers of the ovary, endometrium, bladder, lung, colon, and head/neck. The introduction of HER2-directed therapies has dramatically influenced the outcome of patients with HER2-positive breast and gastric/gastroesophageal cancers; however, the results have proved disappointing in other HER2-overexpressing cancers [49]. The association between HER2 and platinum resistance in breast cancer cells [50] and the data of a systematic review suggest that triple-negative breast cancer have increased sensitivity to platinum-based chemotherapy [51]

In CCC

Amplification and overexpression of HER2 have been described in 14–42.9 % of Ovarian CCC cases [52, 53]. However, no report to date has investigated the association between HER2 and mechanisms of platinum resistance in CCC