Abstract
Hepatocellular carcinoma (HCC) is a disease with a high incidence and mortality rate worldwide. However, the mechanisms underlying its pathogenesis are still elusive. In recent years, studies on functions of Krüppel-like factors (KLFs) in HCC have shed new light on this field. To date, five members (KLF4, KLF6, KLF8, KLF9, and KLF17) in the KLF family have been reported to function in the pathogenesis of HCC in multiple ways, which hold the potential of deepening and widening our understanding in the initiation and progression of HCC. In this review, we focus on the functions, roles, and regulatory networks of these five KLFs in HCC, summarize key pathways, and propose areas for further investigation, with the hope that this review will provide a reliable and concise reference for readers interested in this area.
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Introduction
The Krüppel-like factor (KLF) gene was first found in Drosophila melanogaster, the inactivation of which causes a crippled phenotype in flies. That is why it is termed “Krüppel.” In 1993, the first mammalian homologue to the D. melanogaster Krüppel gene was identified in a murine erythroleukemic cell line and was named erythroid Krüppel-like factor (E-KLF, also known as KLF1) [1]. Two years later, KLF1 was reported to trans-activate β-globin expression via binding to the CACCC element within its promoter [2] and be indispensable during early fetal liver erythropoiesis in a mouse model [3]. Since then, a diverse family of homologous genes has been discovered, now known as the KLF family. To date, this family comprises 17 identified members (KLF1-17), which were numbered sequentially by the Human Genome Organization Gene Nomenclature Committee (HGNC) in order of their discovery.
KLFs are a family of zinc finger transcription factors that control essential cellular processes such as proliferation, differentiation, and migration [4]. Structurally, the KLF family members have a highly conserved C-terminal region composed of triple zinc fingers with DNA-binding activity, while their N-terminal regions are highly divergent [5, 6] (Fig. 1a). Consequently, different KLF members can recognize similar target sequences (preferentially “GC box” or “CACCC” elements), while their divergent N-terminus may permit the binding of different coactivators, corepressors, or other cofactors, leading to functional diversity [4]. KLF family members have been reported to be involved in the pathogenesis of many cancers, such as KLF2 in colon [7] and breast cancer [8], KLF5 in esophagus [9] and lung cancer [10], and KLF10 in pancreas [11] and kidney cancer [12].
Hepatocellular carcinoma (HCC) is one of the most common cancers as well as the leading cause of cancer death both in men and in women worldwide [13]. According to an epidemiological study in the USA [14], the 5-year relative survival rates for localized liver cancer have doubled during the last two decades. However, this advancement is mainly attributed to the improvement in surveillance and surgery, rather than in drug therapy [14]. The relatively slow advancement in HCC drug therapy is, at least partially, due to the elusiveness of its pathogenesis. Therefore, the identification of related genes and pathways underlying HCC initiation and progression is of vital importance to rein in this cancer.
To date, there are five members in the KLF family that have been reported to function in HCC (Table 1). In this review, we focus on the functions of these five KLFs in HCC, summarize key pathways in these functions, and propose possible areas for further investigation.
KLF4 in HCC
KLF4 is one of the key factors in induced pluripotent stem cell (iPSC) technology [15]. It can bi-directionally regulate genes involved in cell cycle regulation and epithelium differentiation [16]. And coincidently, KLF4 can be oncosuppressors or oncogenes, depending on tumor types. It functions as an oncogene in malignant tumors such as B non-Hodgkin lymphoma [17], whereas in many epithelial cancers such as colon, esophageal, gastric, bladder, pancreatic, and lung cancer, KLF4 functions as a tumor suppressor [18–24].
As for the role of KLF4 in HCC, except for one study [25] showing that high KLF4 level is associated with vascular invasion and poor survival, the majority of evidences support its oncosuppressive role in HCC. Hsu HT et al. [26], for example, showed that a high cytoplasmic KLF4 level in cancerous tissues from HCC patients was correlated with better survival. A study by Lin ZS et al. [27] showed that KLF4 inhibits tumor proliferation, migration, and invasion in MM189 cells (a murine HCC cell line) and a xenograft model. Subsequent mechanism investigation revealed that KLF4 binds and represses the promoter of the SLUG, a critical transcription factor involved in epithelial-mesenchymal transition (EMT). As we know, EMT plays a vital role in cancer metastasis; thus, SLUG may be the downstream effector of KLF4-mediated oncosuppression [27].
Another study [28] using human HCC samples and cell lines to investigate the role of KLF4 in HCC gained similar results as above but had three noteworthy new findings. Firstly, KLF4 was identified as a prognostic marker (decreased KLF4 was significantly associated with reduced patients’ survival span). Secondly, hyper-methylation of the exon 1 region of KLF4 is associated with reduced KLF4 expression. And thirdly, vitamin D receptor (VDR) was identified as a transcriptional target of KLF4. KLF4 activates VDR expression and therefore enhances the growth inhibitory effect of vitamin D3 on HCC cells [28].
KLF6 in HCC
The structure of KLF6 protein is shown in Fig. 1b. It is a protein encoded by four exons (Fig. 1c) at chromosome 10p15. As shown in Fig. 1c, alternative splicing of KLF6 gene generates three variants termed splicing variant 1 (SV1), SV2, and SV3. KLF6 protein is expressed from very early stages during human placental development and is indispensable for fetus development. KLF6 knockout causes embryonic death in mice due to multiple lethal developmental defects such as impaired placental development, poorly defined liver, and failures in yolk sac vascularization [29].
KLF6 gene in general is regarded as a tumor suppressor in a diversity of malignant tumors such as prostate carcinoma, glioblastoma, colorectal cancer, and HCC [30]. But if it is aberrantly spliced, the resultant splice variants may have different roles from their wild-type counterpart in tumorigenesis [31–33].
Roles and functions of KLF6 and its splicing variants in HCC
Among the members of the KLF family, KLF6 represents the most studied one in HCC. As shown in Fig. 1c and Table 2, KLF6 has three SVs that play different roles in HCC. Generally, KLF6 SV1 is regarded as an oncogene [34, 35]. However, the roles of wild-type KLF6 (wt-KLF6) and KLF6 SV2 are somewhat controversial. Zhenzhen Z et al. [36] reported that the expression level of KLF6 SV2 was higher in HCC tissues and cell lines compared with the control, whereas a study by Hanoun N et al. [37] demonstrated anti-proliferation and pro-apoptosis effects of KLF6 SV2 in HCC. As for wt-KLF6, two studies conducted by Sirach E et al. in 2007 [38] and Bureau C et al. in 2008 [39] reported that KLF6 was overexpressed in HCC. Sirach E et al. [38] found that in liver cancer cell lines, KLF6 knockdown had anti-proliferative and pro-apoptotic effects by inhibiting Rb phosphorylation and Bcl-xL expression. However, the siRNA sequences used in this study overlap significantly with the common sequences of wt-KLF6 and its variants. So, the anti-cancer effects of KLF6 knockdown might be, at least partially, attributed to the non-specific knockdown of KLF6 SV1 [38]. However, apart from these two studies, the majority of other studies reported it as an oncosuppressor, with anti-proliferation, pro-apoptosis properties in HCC cell lines and tissues [36, 37, 40–46]. In recent years, there seems to be a consensus to regard KLF6 as an oncosuppressor in general [30–33].
KLF6 loss of heterogeneity and mutations
As stated above, the wt-KLF6 gene is generally an oncosuppressor. However, it can be inactivated by somatic mutations or loss of heterozygosity (LOH) during tumorigenesis [31]. Studies on KLF6 mutations or LOH in HCC are displayed in Table 3. As shown in this table, Kremer-Tal S and colleagues found that of 41 HCC patients, 39 % showed KLF6 LOH and 15 % showed mutations [40]. However, other studies failed to observe such a phenomenon [38, 39, 47, 48]. So, present evidences do not support a significant role of KLF6 LOH and/or mutations in hepatocarcinogenesis.
Upstream regulators and downstream effectors/targets of KLF6 and its SV in HCC
Table 4 and Fig. 2 present upstream regulators and downstream effectors/targets of KLF6 and KLF6 SVs in HCC. As shown in Table 4, p21, a famous tumor suppressor, is a downstream target of KLF6 and its SVs [35, 37, 42, 43, 49, 50]. wt-KLF6 and KLF6 SV2 increase p21 expression [37, 43, 50] whereas SV1 inhibits p21 expression [35]. Apart from p21, KLF6 and its SVs also regulate a handful of other genes that are involved in HCC tumorigenesis, such as tumor suppressor genes (E-cadherin and p53), oncogenes (Rb, β-catenin, pituitary tumor-transforming gene 1 (PTTG1), and MDM2), pro-apoptosis gene (Bax), and anti-apoptosis gene (Bcl-xL) [38, 41, 44, 46]. For example, PTTG1, an oncogene in HCC, was transcriptionally repressed by KLF6. KLF6 knockdown promoted HCC cell proliferation, at least partially resulting from PTTG1 upregulation [44].
Regulation of variant splicing of KLF6 in HCC
As stated above, in tumorigenesis, wt-KLF6 and its SVs play different roles and can interact with each other. For example, KLF6 SV1 can promote KLF6 degradation and antagonize its transcriptional activation on p21 gene [34]. However, our knowledge on regulatory pathways involved in KLF6 variant splicing is still in its infancy. A previous study in prostate cancer revealed that a single nucleotide polymorphism (SNP) within KLF6 intron 1 leads to an elevated oncogenic SV1 level [6]. Muñoz Ú et al. reported that in HepG2 cells, hepatocyte growth factor (25 ng/mL) treatment leads to increased ratio of SV1/KLF6, via Akt phosphorylation and the resultant downregulation of SRSF3 and SRSF1 (two splicing regulators) [35]. The activation of Ras and its downstream effector PI3K was also reported to increase SV1 messenger RNA (mRNA) level in HCC cell lines [49]. The 3′ untranslated region (3′ UTR) of KLF6 mRNA is another participant in KLF6 alternative splicing [51]. Further studies are needed to depict a more comprehensive profile of regulatory pathways governing KLF6 variant splicing in HCC.
KLF8 in HCC
Existing evidences suggest that KLF8 functions as an oncogene in HCC [52, 53].
The first research on KLF8 in HCC was conducted by Li JC et al. [52] in 2010, in which KLF8 mRNA expression was found to be positively correlated with the metastatic potential of HCC cell lines as well as with the disease progression of HCC patients. This research demonstrated that KLF8 promotes cancer proliferation and invasion both in vitro and in vivo and that KLF8 inhibits apoptosis in HCC cell lines by transactivating cyclin D1 and Bcl-xL gene. Moreover, KLF8 knockdown by RNA interference resulted in EMT inhibition, with downregulation of mesenchymal markers (N-cadherin, vimentin, and fibronectin) and upregulation of the epithelial marker (E-cadherin). In 2012, Yang T et al. confirmed the positive correlation between KLF8 protein levels and HCC progression and proposed a reciprocal crosstalk between KLF8 and Wnt signal pathway [53].
KLF9 and KLF17 in HCC
Up to now, limited evidences showed that KLF9 and KLF17 play oncosuppressive roles in hepatocarcinogenesis.
Fu DZ and colleagues [54] reported that KLF9 mRNA and protein levels were decreased in HCC tissues compared with normal liver tissues and that the upregulation of KLF9 expression has anti-proliferation and pro-apoptosis properties in HepG2 cells. A recent study by Sun J et al. [55] gained similar results but went further. They found that by binding to the p53 promoter, KLF9 upregulates p53 levels and that KLF9 overexpression significantly promotes tumor regression in the xenograft model. These two studies suggest the oncosuppressive role of KLF9 in HCC, which, however, needs to be confirmed by more studies in the future.
As for KLF17, Liu FY and his team [56] in 2013 reported that a decreased expression level of KLF17 was correlated with reduced survival span of HCC patients and resulted in increased invasive capacities of HepG2 cells as well as altered expression levels of several genes that are involved in EMT (such as E-cadherin, ZO-1, Snail, and vimentin). A study by Sun Z et al. [57] showed that KLF17 inhibited HCC cell invasion and migration possibly via counteracting EMT (Table 5).
Perspectives and conclusion
Possible involvement of other KLF family members in hepatocarcinogenesis
There are 17 KLF family members that have been identified to date, the majority of which have been reported to function in tumors (Tables 1 and 6). However, there are only five KLFs that have been reported to function in HCC (Table 1). As we know, genome instability and mutations are the underlying mechanisms of many, if not all, cancers. As a result, different cancers may share common signaling pathways and pathological mechanisms. Therefore, it is reasonable for us to anticipate that in the near future, there will be other KLF family members that are found to function in HCC.
Clarifying KLF regulatory networks
As shown in Tables 4 and 5, genes that are most frequently regulated by KLFs are EMT-related genes, such as Slug, vimentin, fibronectin, and E-cadherin. In addition, apoptosis-related genes such as Bcl-xL and Bax and oncosupressors such as p21 and p53 are also under the regulation of KLFs. These HCC-related KLFs, along with their downstream gene pools, construct regulatory networks that are potential tumor biomarkers and/or therapeutic targets.
However, as shown in Tables 4 and 5, our current knowledge on the regulatory network of KLFs is fragmental rather than comprehensive. Further researches are needed to picture the regulatory networks of KLFs in HCC so as to advance our understanding of the pathogenesis of this deadly disease.
As stated above, there are five members of the KLF family that have been reported to function in HCC; then, how do they interact with each other? And what roles does this interaction network play in HCC pathogenesis? The solution of these problems may provide opportunities for the development of novel diagnostic biomarkers and therapeutic targets.
To sum up, studies on KLFs in HCC gave us new insight into the mechanisms of this deadly disease and, in the meanwhile, presented us many challenges and yet-to-be-resolved questions. One question was resolved and more emerged; this may be the essence and charisma of scientific researches.
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National High Technology Research (863) Project of China (2012AA020204).
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Xiao-Jie Lu and Yan Shi contributed equally and are co-first authors.
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Lu, XJ., Shi, Y., Chen, JL. et al. Krüppel-like factors in hepatocellular carcinoma. Tumor Biol. 36, 533–541 (2015). https://doi.org/10.1007/s13277-015-3127-6
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DOI: https://doi.org/10.1007/s13277-015-3127-6