The Role of circHIPK3 in Human Cancers: History
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Contributor:
Yanfei Feng
,
Zitong Yang
,
Bodong Lv
,
Xin Xu

Circular RNAs (circRNAs) are a class of noncoding RNAs with closed-loop of single-stranded RNA structure. Although most of the circRNAs do not directly encode proteins, emerging evidence suggests that circRNAs play a pivotal and complex role in multiple biological processes by regulating gene expression. Accumulating studies have substantiated that the dysregulation of circular homeodomain-interacting protein kinase 3 (circHIPK3) contributes to multiple processes in the carcinogenesis and progression of various human cancers. Not only does this molecule play a pivotal role in the proliferation, migration, invasion, and drug resistance of tumor cells, but also it has the potential to act as a biomarker in early diagnosis and prognosis, considering that in most cases, circHIPK3 is a tumor promoter by sponging miRNAs.

  • lung cancer
  • ESCC
  • circHIPK3

1. Lung Cancer 

As one of the most life-threatening human malignancies, lung cancer has been a global challenge during the past years [1]. Several published reports have provided us some novel clues of the occurrence and progression of lung cancer (LC) mediated by overexpressed circular homeodomain-interacting protein kinase 3 (circHIPK3). Yu and colleagues elucidated that enriching circHIPK3 facilitated the expression of sphingosine kinase 1 (SphK1), cyclin-dependent kinase 4 (CDK4), and signal transducer and activator of transcription 3 (STAT3) through impeding miR-124 in lung cancer cells, and accelerating LC cell growth [2]. Chen et al. also illustrated another signaling pathway mediated by circHIPK3/miR-124-3p. STAT3 was reported to be the downstream target of miR-124-3p in this case [3]. Lu and others explored another miRNA which was involved in the carcinogenesis and progression of nonsmall-cell lung cancer (NSCLC) mediated by circHIPK3. Their research revealed that circHIPK3 negatively regulated miR-149, promoting forkhead box M1 (FOXM1) expression. Eventually, cell proliferation was triggered when apoptosis was blocked [4]. MiR-107 was introduced by Hong and colleagues indicating that circHIPK3 downregulated miR-107, reversing its inhibitive effect on brain-derived neurotrophic factor (BDNF), which facilitated NSCLC progression [5]. However, Zhao et al. observed a lower expression level of circHIPK3 in LC specimens compared with surrounding nontumor tissues. Moreover, patients with lower circHIPK3 were more likely to have larger tumor size, more advanced TNM stage, and more lymph node infiltration. Further experiments on gefitinb-resistant cell line revealed that low circHIPK3 contributed to gefitinib resistance [6].

2. Hepatocellular Carcinoma 

Hepatocellular carcinoma (HCC) is a common malignancy with high recurrence and mortality rate around the world [1]. An augmented level of circHIPK3 in HCC was validated in several studies. Chen and colleagues observed that the increased level of circHIPK3 was positively associated with Aquaporin 3 (AQP3) expression in HCC specimens. Mechanistically, miR-124 was considered as an intermediate link between circHIPK3 and AQP3. Intriguingly, the aberrant expression of circHIPK3 was closely correlated with several clinical parameters such as tumor stage, the amount of HBV–DNA copy and the existence of liver cirrhosis in patients with HCC [7]. MiR-124 was also confirmed as the target of circHIPK3 in other studies. Yu et al. observed that the upregulation of circHIPK3 was associated with depletion of miR-124 and miR-506. Pyruvate dehydrogenase kinase 2 (PDK2) was reported to be the downstream target of miR-124 or miR-506. The circHIPK3-miR-124/miR506-PDK2 signaling gave rise to carcinogenesis and progression of HCC cells [8]. Hu and others demonstrated the expression of miR-124-3p and miR-4524-5p was inhibited by circHIPK3, promoting multidrug-resistant protein 4 (MRP4) expression. Although their findings suggested MRP4 was not directly involved in occurrence and progression of HCC, MRP4 itself was proved to be aberrantly overexpressed in multiple cancers [9]. Another miRNA involved in the association between circHIP3 and HCC was miR-338-3p introduced by Li et al. Similarly, circHIPK3 served as the sponge of miR-338-3p, hindering zinc finger E-box binding homeobox 2 (ZEB2) expression. This signaling eventually led to epithelial–mesenchymal transition (EMT) and HCC metastasis [10].

3. Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) is a malignancy of the digestive system which severely affects quality of life [1]. Yao et al. reported that an elevated level of circHIKP3 in ESCC cells remarkably absorbed miR-599 expression and significantly stimulated c-MYC expression, leading to cell growth and metastasis [11]. Yao and colleagues validated that miR-124 functioned as the sponged miRNA in this case and serine/threonine kinase 3 (AKT3) was enhanced under the modulation of circHIPK3, which further triggered ESCC cell growth and metastasis [12].

4. Gastric Cancer 

The incidence of gastric cancer (GC) has been gradually escalating during the past decades [1]. Most of the emerging studies demonstrated an overexpression of circHIPK3 in GC cells. Cheng et al. discovered that circHIPK3 was even higher in metastatic GC cells. They further unveiled the underlying mechanisms that circHIPK3 suppressed the expression of miR-29b and miR-124, enhancing GC cell replication. Furthermore, this signaling pathway was considered to be a prognostic factor of GC [13]. Wei et al. elucidated the connections between circHIPK3 (level, stage, grade) and the prognosis of GC. Knocking down circHIPK3 significantly extenuated GC progression by upregulating miR-107 and then depleted brain-derived neurotrophic factor (BDNF) [14]. Another miRNA introduced by Li and others was miR-876-5p. Their research showed that circHIPK3 sponged miR-876-5p, reversing its inhibitive effects on phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), an oncogene proved to exist in multiple tumors, including GC [15]. A study conducted by Jin et al. illustrated that circHIPK3 contributed to metastatic disease of GC by downregulating miR-653-5p and miR-338-3p. Neuropilin 1 (NRP1) was determined as the inhibited target downstream of these two molecules and its depletion stimulated extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) pathways [16]. Yang et al. observed another regulatory pathway in which circHIPK3 suppressed miR-637, rescuing the function of serine/threonine kinase 1 (AKT1) sabotaged by miR-637 and then enhancing GC cell progressive activities [17]. Liu and colleagues observed that silencing circHIPK3 decreased GC cell proliferation and migration. The Wnt/β-catenin pathway was considered as the intermediate factor of this process [18]. However, Ghasemi and colleagues arrived at a contrary conclusion, that a dramatically decreased level of circHIPK3 in GC was proved to be associated with patient age and clinical stage [19]. The conflicting conclusions drawn by different scientists made the role of circHIPK3 in GC more complicated.

5. Colorectal Cancer 

Colorectal Cancer (CRC) is another most common gastrointestinal cancer which hugely affects quality of life [1]. A study organized by Zeng et al. clarified that an augmented level of circHIPK3 in CRC cells blocked miR-7 expression and then contributed not only to the activation of cell proliferation and metastasis, but also inhibits cell apoptosis [20]. Yan et al. also discovered an increase in circHIPK3 level in CRC cells. Another miRNA was introduced by them, miR-1207-5p, which was negatively regulated by circHIPK3 and whose inhibitive effects on formin-like 2 (FMNL2) were relieved. This signaling pathway consequently resulted in CRC cell replication and metastasis [21]. Zhang et al. explored the oxaliplatin-resistant mechanisms of CRC and demonstrated that circHIPK3 acted as the sponge of miR-637 to enhance STAT3 expression, triggering Bcl-2/beclin1 afterward, and as a result detecting decreased autophagy. Additionally, they observed connections between an elevated level of circHIPK3 and clinical indicators of poor prognosis [22].

6. Prostate Cancer 

The incidence of prostate cancer (PCa) ranks first in men [1], in which an unregulated level of circHIPK3 was validated in several studies. In the research of Chen et al., circHIPK3 was identified as a crucial factor of prognosis. Via sponging miR-193a-3p, circHIPK3 promoted myeloid cell leukemia 1 (MCL1) expression, and activated PCa cell growth and tumor progression [23]. Cai and colleagues demonstrated that the enrichment of circHIPK3 stimulated the proliferation and invasion of PCa cells by impeding miR-338-3p and strengthening a disintegrin and metalloproteinases 17 (ADAM17) expression [24]. Another study by Liu et al. identified other downstream molecules of miR-338-3p as Cdc2 and Cdc25B and this signaling pathway modulated by circHIPK3 led to acceleration of G2/M transition and the proliferation of PCa cells [25]. Liu and others uncovered another pathway mediated by circHIPK3 in which circHIPK3 downregulated miR-448 to activate metadherin (MTDH), thus accelerating PCa cell proliferation and metastasis [26]. Tang et al. identified an overexpression of exosomal circHIPK3 in PCa, which suppressed exosomal miR-212 and relieved its negative modulation on B-cell-specific MMLV insertion site-1 (BMI-1), consequently activating cell growth and metastasis [27].

7. Renal Cell Carcinoma 

Renal cell carcinoma (RCC) is one of the urinary cancers with high prevalence [1]. Lai and colleagues detected that an elevated expression of circHIPK3 in RCC cells blocked the function performed by miR-485-3p on several molecules related to EMT and cell death. For example, the overexpression of clever caspase-3, Bax, and E-Cadherin was hampered and the decrease in Vimentin, N-Cadherin, and Bcl-2 was reversed [28]. Han et al. verified that by hindering expression of miR-508-3p, the increased level of circHIPK3 boosted RCC cell viability. The downstream target of miR-5083p was determined as chemokine ligand 13 (CXCL13), whose activation was also validated to be associated with several cancers [29]. Omata and others discovered an upstream regulator of circHIPK3 as adenosine deaminase acting on RNA 1 (ADAR1), which could inhibit circHIPK3 and then activate miR -381-3p, so as to block the translation process of MRP4 protein, a factor which was clarified to be related with drug resistance [30]. On the contrary, Li et al. elaborated that circHIPK3 was sharply diminished in RCC cells, and that lifting circHIPK3 expression repressed the invasiveness of RCC cells by hampering miR-637 [31].

8. Bladder Cancer

Bladder cancer is another frequently diagnosed cancer of the urinary system [1]. Compared with other malignancies, circHIPK3 tended to be downregulated in bladder cancer cells. Li et al. showed that circHIPK3 expression was negatively associated with clinical stage, invasiveness, and lymph node infiltration in bladder cancer patients. Mechanistically, circHIPK3 sponged miR-558 to hinder heparanase (HPSE) expression, reducing the development of bladder cancer cells [32]. Xie and colleagues clarified the prognostic value of circHIPK3 in bladder cancer and illustrated that an elevated expression of circHIPK3 enhanced the response to gemcitabine chemotherapy [33]. Remarkably, the analysis conducted by Okholm et al. demonstrated that circHIPK3 was rigidly related with aggressiveness in nonmuscle-invasive bladder cancer, further highlighting the prognostic role of circHIPK3 in bladder cancer [34].

9. Breast Cancer

Breast cancer has created onerous economic and social burden owing to its high prevalence in females [1]. Qi and colleagues along with Luo et al. detected an aberrantly elevated expression of circHIPK3 in breast cancer. The downstream target of circHIPK3 was considered to be miR-326, and the depletion of miR-326 mediated by circHIPK3 resulted in cell replication, migration, and invasion of breast cancer [35][36]. Shi et al. demonstrated that an upregulated circHIPK3 targeted miR-124-3p to boost MTDH expression, facilitating angiogenic activities of breast cancer cells [37]. Chen et al. identified miR-193a as another target of circHIPK3. Further, the signaling pathway went downstream to high mobility group box-1 (HMGB1)/phosphoinositide-3-kinase (PI3K)/AKT and the proliferative and metastatic abilities of breast cancer cells were enhanced as a consequence [38]. Zhang et al. offered deep insight into the mechanisms of trastuzumab resistance in breast cancer and discovered that exosomal circHIPK3 was capable of lowering the sensitivity of breast cancer cells to trastuzumab [39]. A study managed by Ni and colleagues revealed another phenomenon of chemoresistance in which circHIKP3 overexpression suppressed miR-1286 to enhance hexokinase 2 (HK2) expression and decreased the response to paclitaxel treatment in breast cancer cells [40].

10. Ovarian Cancer 

Ovarian Cancer (OC) is not uncommon in the female genital system [1]. Liu et al. uncovered that circHIPK3 expression was hugely increased in OC tissues and cell lines, which was considered to correlate with unfavorable outcomes of OC [41] as well. However, Teng and colleagues detected a reduction in circHIPK3 level in OC cells. CircHIPK3 depletion was validated to stimulate cell growth, invasion, and migration, on the one hand, and, on the other, prevent cell death. A number of miRNAs, such as miR-10a, miR-106a, and miR-148b, were assumed to be modulated in this process, but exactly which miRNAs were inhibited remained elusive [42].

11. Cervical Cancer 

Cervical cancer, one of the most common genital cancers in postmenopausal women, usually causes poor outcomes [1]. Wu and colleagues observed a dramatically upregulated status of circHIPK3 in CC cells. The miRNA sponged by circHIPK3 was reported to be miR-485-3p, and its depletion accelerated fibroblast growth factor 2 (FGF2) expression, strengthening the tumorigenic and progressive abilities of CC cells [43]. Qian et al. validated miR-338-3p as another molecule inhibited by circHIPK3. Accordingly, hypoxia-inducible factor-1alpha (HIF-1α) activated and triggered EMT to stimulate CC cell proliferation, migration, and invasion [44].

12. Osteosarcoma

Osteosarcoma is a type of severe disease frequently diagnosed in youngsters [1]. Huang and colleagues demonstrated an augmented expression of circHIPK3 in osteosarcoma cells, which downregulated miR-637, relieved its negative regulation on STAT3, and caused osteosarcoma cell metastasis [45]. Similarly, Wen et al. introduced another signaling pathway in which circHIPK3 mediated osteosarcoma progression by decreasing miR-637 to facilitate histone deacetylase 4 (HDAC4) expression [46]. However, Ma et al. observed a strikingly decreased level of circHIPK3 in osteosarcoma cells and specimens, which correlated with an advanced stage, distant metastasis, and unfavorable prognosis. While a higher circHIPK3 expression dramatically declined aggressiveness of tumor cells [47], the contradictory conclusions obtained by these studies requires further exploration.

13. Glioma

With unfavorable prognosis, glioma is one of the most malignant tumors in the central nervous system [1]. Emerging published reports clarified an increased level of circHIPK3 in glioma cells. Jin et al. validated that circHIPK3 promoted insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) expression by blocking miR-654, which expanded the proliferative and metastatic capabilities of glioma cells [48]. Hu and colleagues demonstrated that a high expression level of circHIPK3 significantly suppressed miR-124-3p to rescue its negative effects on STAT3. This pathway had a promotive influence on tumorigenesis and progression of glioma cells [49]. Another target of circHIPK3/miR-124 interaction determined by Liu et al. was cyclin D2 (CCND2), which again spurred the development of glioma [50]. CircHIPK3 was also considered to be inextricably bound with temozolomide treatment of glioma, and two signaling pathways were introduced by scientists. One study of Han et al. verified that exosomal circHIPK3 reduced the sensitivity to temozolomide treatment via absorbing the effect of miR-421 and triggering zinc finger of the cerebellum 5 (ZIC5) expression [51]. The other study conducted by Yin and colleagues identified miR-524-5p as the direct target of circHIPK3 and kinesin family member 2A (KIF2A) the downstream molecule [52].

14. Oral Squamous Cell Carcinoma 

Oral Squamous Cell Carcinoma (OSCC) is a particularly severe malignant tumor with poor outcomes that occurs in the regions of head and neck [1]. Bi et al. uncovered the enhanced expression of circHIPK3 in OSCC and clarified its further target molecule as miR-381-3p. Yes-associated protein1 (YAP1) was determined to be the downstream factor whose upregulation stimulated the carcinogenesis and progression of OSCC cells [53]. Similarly, the findings of Jiang et al. suggested that miR-637 was negatively modulated by augmented circHIPK3, triggering nuclear protein 1 (NUPR1) and PI3K/AKT pathway to activate OSCC cell growth and metastasis [54].

15. Leukemia

The incidence of leukemia has been increasing during the past years [1]. Feng et al. found that circHIPK3 was enormously overexpressed in the blood cells and serum of chronic myeloid leukemia (CML), suggesting a worse outcome [55]. Similarly, Gaffo and colleagues detected an abnormally increased expression of circHIPK3 in acute lymphoblastic leukemia (ALL) cells, which provided novel findings in this issue [56].

16. Other Cancers

Apart from those mentioned, there have been connections between circHIPK3 and other cancers including nasopharyngeal cancer (NPC), pancreatic cancer, thyroid cancer, gallbladder cancer (GBC), melanoma, and glioblastoma. Ke et al. revealed an augmented expression of circHIPK3 in NPC and a dramatically declined miR4288 expression. Mechanistically, circHIPK3 blocked miR4288 in order to boost the expression of E74-like ETS transcription factor 3 (ELF3), and promote NPC cell growth [57]. In terms of pancreatic cancer, Liu and colleagues demonstrated that the overexpression of circHIPK3 remarkably downregulated miR-330-5p-activated RAS-association domain family 1 (RASSF1) expression, stimulating the carcinogenesis and progression and becoming immune to gemcitabine therapy of pancreatic cancer cells [58]. Shu et al. showed an aberrantly increased circHIPK3 level in thyroid cancer cells and identified miR- 338-3p as the downstream sponged factor. Ras-like in rat brain 23 (RAB23) was enhanced under the modulation of circHIPK3, which contributed to tumorigenesis and progression of thyroid cancer cells [59]. Regarding GBC, circHIPK3 expression was found significantly higher in GBC cells by Kai and colleagues. MiR-124 was considered to be sharply suppressed by circHIPK3, escalating the expression of rho-associated protein kinase 1 (ROCK1) and cyclin-dependent kinase 6 (CDK6), which caused the accelerated growth of GBC cells [60]. Zhu et al. observed that circHIPK3 was remarkably overexpressed in melanoma cells and the downstream target molecule was confirmed to be miR-215-5p, the depletion of which significantly triggered Yin Yang 1 (YY1) expression and thereby expedited cell growth and mitigated cell death of melanoma [61]. Stella and colleagues discovered correlations between the reduction in circHIPK3 in serum extracellular vesicle and the prognosis of glioblastoma and suggested that circHIPK3 could possibly serve as a promising biomarker [62].

This entry is adapted from the peer-reviewed paper 10.3390/diagnostics12102469

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