Wnt5a: A promising therapeutic target in ovarian cancer

Abstract

Despite the rapid development of novel adjuvant and neoadjuvant chemotherapeutic drugs in recent years, advanced ovarian cancer still lacks effective treatment strategies and remains one of the main causes of death among women. Wnt protein family is widely expressed in a variety of human tissues, and Wnt5a is an important member of the noncanonical Wnt pathway. Wnt5a has been found to induce tumor suppression as well as to function as an oncogene depending upon the specific cancer type. In ovarian cancer, Wnt5a protein expression has been observed to be significantly upregulated and associated with poor prognosis. Researchers found that downregulating Wnt5a expression levels effectively suppresses ovarian cancer cell migration and invasion abilities. We believe that the downregulation of Wnt5a will be an attractive and promising antimetastatic therapeutic approach for the future treatment of patients with advanced ovarian cancer. The present review focuses on the mechanisms and therapeutic potential of Wnt5a as a promising novel therapeutic target for ovarian cancer.

Introduction

The Wnt protein family was originally identified in mouse breast cancer and is widely expressed in a variety of human tissues [1]. It is a large family of secreted glycoproteins and regulates cell proliferation, differentiation, migration, polarity and death during embryonic development. There are 19 Wnt family members found in mammals, including Wnt1, Wnt2, Wnt3, Wnt4, and Wnt5a, among others [2].

There are 3 different Wnt pathways [3]: (1) One pathway is the canonical Wnt pathway, also known as the Wnt/β-catenin pathway. In this pathway, the binding of Wnt protein to the Frizzled receptor inactivates the multiprotein destruction complex, causing the aggregation of β-catenin in the cytoplasm. Then, β-catenin enters the nucleus and combines with T cell factor/lymphoid enhancing factor (TCF/LEF), which results in activation of the transcription of downstream target genes (MMP7, c-myc, cyclin D1, etc.) [4]. Abnormal activation of this pathway is closely related to the development of many tumors, such as colon cancer, lung cancer, melanoma, breast cancer, and ovarian cancer. [[5], [6], [7], [8], [9], [10]]. (2) The second pathway is the Wnt/Ca²⁺ pathway. It is activated by Wnt4 and Wnt5a, among others. After binding to the Frizzled-2 receptor, Wnt5a increases the intracellular Ca²⁺ concentration, thereby activating calmodulin-dependent kinase II (CaMKII) and protein kinase C (PKC). Then, PKC and CaMKII inactivate the transcription factor nuclear factor of activated T cells (NFAT) to regulate cell adhesion, migration, and differentiation. Mice with Frizzled-2 deletion or knockout of Wnt5a show symptoms of facial deformity, dwarfism, a short tail, and respiratory problems [11]. Obviously, the Wnt5a/PKCa pathway plays a critical role in certain normal physical processes. (3) The third pathways is the Wnt/PCP pathway. Wnt5a binds to the Frizzled receptor and then activates the intracellular signaling protein dishevelled (Dvl). Dvl activates dishevelled-associated activator of morphogenesis 1 (DAAM1), leading to a small increase in the GTPase RhoA, which activates Rho-associated kinase (ROCK) and results in cytoskeletal reorganization and changes to cell polarity and migration. The second and third pathways are called noncanonical pathways [12].

There are multiple signal transduction methods and pathways in cells and interactions between the various pathways, eventually forming a complex Wnt protein interaction network [[13], [14], [15]].

Wnt5a is an important member of the noncanonical Wnt pathway. It is located at chromosome 3p14-p21 and has a molecular weight of 38 kDa [16]. It can both activate the canonical Wnt/β-catenin pathway and the noncanonical Wnt/Ca²⁺ pathway. The interaction between these two pathways may cause Wnt5a to play different roles in different tumors. In adult T cell leukemia, Wnt5a contributes to the increase in osteolytic bone lesions and hypercalcemia [17]. Scientists have not yet reached a consensus on the role of Wnt5a in bladder cancer [18,19] and breast cancer [20,21]. In cervical cancer, Wnt5a plays a role in promoting cancer and can strengthen the proliferation and invasion of tumor cells [22]. In chronic lymphocytic leukemia, researchers have found that Wnt5a can increase tumor cell proliferation and migration [23]. In classic Hodgkin lymphoma, Wnt5a enhances tumor metastasis [24]. In colon cancer [25] and esophageal cancer [26], Wnt5a is a tumor suppressor gene, yet in gastric cancer [27], it promotes invasion and metastasis. Wnt5a is also an oncogene in several other cancers, including glioblastoma [28], kidney renal clear cell carcinoma [29], liver cancer [30], melanoma [31], nasopharyngeal carcinoma [32], non-small-cell lung cancer [33], pancreatic cancer [34], and osteosarcoma [35]. However, Wnt5a inhibits proliferation, migration and invasion in thyroid cancer [36]. Moreover, researchers have made more interesting discoveries about Wnt5a in prostate cancer. Mikels and Nusse have found out that signaling initiated by Wnt5 is regulated by receptor availability instead of Wnt5a itself, which may produce totally different biological roles even in the same type of cancer [37]. For example, with Frizzled-2 as receptor, overexpression of Wnt5a can enhance invasion activity of prostate cancer cells [38]. On the contrary, Ren et al. have reported that Wnt5a acts as a tumor suppressor, which induces and maintains dormancy of prostate cancer cells in the bone and inhibits bone metastasis of prostate cancer by binding to the receptor-tyrosine-kinase-like orphan receptors 2 (ROR2) receptor [39]. We summarized the role of Wnt5a in different tumors in Table 1.

Researchers have found that Wnt5a protein expression in ovarian cancer is significantly higher than that in benign ovarian tumors and normal ovarian tissues [40]. The differences in prognoses and survival times in patients with different levels of Wnt5a expression suggest that Wnt5a is involved in the progression of ovarian cancer. In this review, we determined the expression level of Wnt5a in ovarian cancer and the effect of Wnt5a on the migration and invasion of ovarian cancer cells. The role of Wnt5a in the metabolism and aging of ovarian cancer cells and its potential therapeutic value are also discussed.