1p22.1

CDC7L1,HsCDC7,Hsk1,huCDC7

Adrenocortical carcinoma

Data mining of gene expression revealed positive regulation of genes involved in DNA damage and cell cycle pathways in samples from adrenocortical carcinoma patients, including CDC7, their higher levels were associated with worse overall survival (Subramanian and Cohen, 2019).

Bladder cancer

In order to identify candidate genes associated with cisplatin-resistant bladder cancer cells, sensitive and cisplatin-resistant cell lines were used for microarray analysis to determine the differential expression of significant genes in resistance. A total of 18 genes, including CDC7, were significantly upregulated in cisplatin-resistant cell lines (Kim et al., 2016).

Breast Cancer

In breast cancer, high CDC7 expression had been reported (Bonte et al., 2008; Zografos et al., 2019), and associated with the development of aggressive disease, including ERBB2 (HER2) overexpression, triple-negative subtypes, accelerated cell cycle progression, disrupted tumor differentiation, genomic instability, increased NPI score, and reduced disease-free survival (Rodriguez-Acebes et al., 2010). Using tissue microarray of a cohort of 2197 highly characterized breast carcinomas, CDC7 expression was found in 1088 samples (57%), of which 228 samples exhibited moderate or strong expression. High CDC7 levels were also related to medullary histotype, high tumor grade, estrogen receptor-negative status, high Ki67 expression; overexpression of TP53 and CDKN2A; and amplification of HER2, MYC, MDM2, CCND1, and ESR1, unfavorable tumor phenotype, and poor prognosis (Choschzick et al., 2010).
In triple negative breast cancer cellular models, the dual CDC7/CDK9 inhibitor (PHA-767491) synergizes with tyrosine kinase inhibitors to overcome resistance to EGFR -targeted therapy (McLaughlin et al., 2019): combined inhibition of EGFR and CDC7/CDK9 reduced cell proliferation accompanied by apoptosis induction, G2/M cell cycle arrest, and DNA replication inhibition.
Due to the rarity of male breast cancer (MBC), serum protein alterations have not been extensively studied. Using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time mass spectrometry (MALDI-TOF MS), a panel of differentially expressed serum proteins were identified, which included the high CDC7 expression in MBC patients (Zografos et al., 2019).

Clear cell renal cell carcinoma

Ghatalia et al. (Ghatalia et al., 2016) analyzed the gene expression of kinases paired samples from primary and metastatic tumor tissues and found that CDC7 is more expressed in metastatic tumors. Using the Cancer Genome Atlas (TCGA) data, the authors also observed an association between high CDC7 expression and reduced metastasis-free survival (Ghatalia et al., 2016). DISEASE

Cervical intraepithelial neoplasia

Using microarray analysis, CDC7 was found among highly expressed genes in high-grade squamous cervical intraepithelial lesions (Suman and Mishra, 2018).

Colorectal cancer

Bonte et al. (Bonte et al., 2008) reported a high CDC7 expression in 8 of out 10 cases of colorectal cancer. In agreement, Chen et al. (Chen et al., 2013) reported a significantly higher CDC7 mRNA and protein expression in samples from 39 colorectal patients compared to their tumor-adjacent normal colorectal tissues. Analysis of 1800 colorectal carcinomas, by immunohistochemistry and tissue microarray, showed that CDC7 was highly expressed. Of note, CDC7 expression was significantly associated with TP53, suggesting that CDC7 may be a potential target in a subset of tumors with high TP53 expression (Melling et al., 2015). In contrast, loss of CDC7 expression was significantly associated with high tumor stage and grade, but was not related to nodal status. In multivariate survival analysis, strong CDC7 expression was an independent marker of improved patient survival (Melling et al., 2015).

Esophageal squamous cell carcinoma

CDC7 is highly expressed in esophageal squamous cell carcinoma (ESCC) tissues, and that CDC7 knockdown inhibits cell proliferation, migration, and invasion, and induces apoptosis in ESCC cells. In addition, downregulation of CDC7 also partially enhances the chemosensitivity of ESCC cells to cisplatin and 5-fluorouracil, indicating that CDC7 may serve as a potential therapeutic target in ESCC (Cao and Lu, 2019).

Glioblastoma

Inhibition of CDC7 by inhibitor PHA-767491 significantly reduced cell viability, proliferation, migration, invasion, and tumorigenesis, and induced apoptosis in glioblastoma models (Erbayraktar et al., 2016; Li et al., 2018). Li et al. (Li et al., 2018) identified that CDC7 expression was enhanced and functionally necessary for proliferation in glioblastomas, and its high expression was associated with poor prognosis.

Head and neck squamous cell carcinoma

Human papillomavirus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC) that can harbor HPV DNA and it was suggestive that there are biological and clinical differences between HPV positive (HPV +) and negative (HPV -) HNSCC. Slebos et al. (Slebos et al., 2006), comparing gene expression profiles of HPV+ and HPV- tumors, found 91 genes differentially expressed, including high CDC7 expression in HPV+ HNSCC.

Hematological neoplasms

Hess and colleagues (Hess et al., 1998) identified the sequence of encoding human gene CDC7 and reported its overexpression in several types of cancers, including hematological neoplasms. Latterly, it was confirmed by Bont et al. (Bonte et al., 2008) in additional leukemia cellular models.
In chronic lymphocytic leukemia (CLL), CDC7 was expressed and activated in lymph node biopsies. A similar finding was also observed in an in vitro model that partially recapitulates lymph node proliferation centers of CLL. These data suggested a potential role for CDC7 in the aberrant lymph node microenvironment (Natoni et al., 2011). In addition, high CDC7 expression was associated with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) (Hou et al., 2012b; Hou et al., 2011; Krawczyk et al., 2009). In DLBCL cell lines, CDC7 silencing combined with rituximab synergistically increased apoptosis (Hou et al., 2012a).
The dual CDC7/ CDK9 inhibitor, PHA-767491, also induced cell death on a panel of multiple myeloma cell lines and primary patient samples alone or in combination with drugs currently used in the clinics, including the TP53 mutant cells that developed resistance to dexamethasone, melphalan, and doxorubicin. PHA-767491 had the same effect on primary myeloma cells from patients who relapsed with progressive refractory disease. These data suggested that the mechanisms leading to chemoresistance in myeloma may not affect the activity of a dual CDC7/CDK9 inhibitor, thus supporting further evaluation of CDC7 and CDK9 targeting in multiple myeloma (Natoni et al., 2013).
In acute myeloid leukemia (AML), the dual CDC7/CDK9 inhibitor, PHA-767491, downregulated MCL1 and sensitized AML cell lines and primary AML blasts to BCL2 inhibitors, ABT-737 and ABT-199 (O Reilly et al., 2018).

Hepatocellular carcinoma

Using gene expression data sets, Zhuang et al. (Zhuang et al., 2018) detected that expression of various genes, including CDC7, was increased in hepatocellular carcinoma tissues compared to adjacent normal tissues. CDC7 overexpression was correlated with advanced histological grade and/or vascular invasion, and predicted worse overall and disease-free survival in hepatocellular carcinoma patients (Zhuang et al., 2018). It is important to highlight that the CDC7 inhibitor (PHA-767491) had a synergistic antitumor effect with 5-FU, exhibiting stronger cytotoxicity and inducing significant apoptosis in hepatocellular carcinoma cell lines and xenograft models (Li et al., 2015).

Lung cancer

In non-small lung cancer (NSCLC) cell lines and tissue samples, CDC7 expression was highly expressed (Bonte et al., 2008). In agreement, CDC7 was significantly increased in lung adenocarcinoma tissues, as observed by immunohistochemistry and gene expression analysis in lung adenocarcinoma (Cao, 2019). In another study, high CDC7 expression significantly correlates with TP53 mutational status and predicts poor clinical outcomes in lung adenocarcinoma patients. In an experimental lung cancer model, CDC7 was also upregulated by gain-of-function mutant TP53, which induced cell cycle progression and tumorigenesis (Datta et al., 2017).

Melanoma

CDC7 gene is located at chromosome 1p22 band, which was identified as a melanoma susceptibility locus with the high frequency of loss of heterozygosity (Walker et al., 2004). In a series of benign and dysplastic nevi, primary cutaneous melanomas and melanoma cutaneous metastasis samples, CDC7 regulatory subunits, DBF4, were found to be upregulated in malignant tissues (Nambiar et al., 2007), which was associated with shorter relapse-free survival. In the same study, DBF4 depletion reduced melanoma cell survival and proliferation (Nambiar et al., 2007). Clarke and colleagues (Clarke et al., 2009), using a tissue microarray containing 40 melanomas, 40 Spitz tumors, and 30 nevi reported that invasive melanomas and atypical Spitz nevi exhibited the highest CDC7 expression.
In order to better understand the transcriptional regulation cell cycle checkpoints in melanocytes and melanoma cell lines, Kaufmann et al. (Kaufmann et al., 2008) analyzed global gene expression patterns upon DNA damage induced by ionizing radiation, and most melanoma cell lines (11 of out 16) showed significant defects in checkpoints, which included reduced expression of TP53 transcriptional targets, and enhanced expression of proliferation-associated genes. Of note, defective melanomas at checkpoint G1 exhibited higher levels of DNA synthesis-related genes, including CDC7 and CKS1B.
Using a VSV-cDNA library and B16 melanoma tumors, CDC7 was identified (among others) as a potential immunogenic antigen for chemotherapy or immunotherapy (Zaidi et al., 2015).

Oral squamous cell carcinoma

Evaluating CDC7 protein expression, by immunohistochemistry, in a cohort of 105 oral squamous cell carcinoma (OSCC) tumors and 30 benign oral tissues, CDC7 overexpression was found in 91% of tumor cases and 1% benign cases (Cheng et al., 2013). In multivariate analysis, CDC7 was an independent marker for overall survival in a cohort of 80 OSCC patients. In OSCC cell lines, overexpression of CDC7 inhibited genotoxin-induced apoptosis, suggesting that high CDC7 expression increases chemotherapy resistance (Cheng et al., 2013). Yong-Deok and colleagues (Yong-Deok et al., 2015) investigated the expression of inflammation-associated genes in samples from tumor and normal tissue from OSCC patients, in which genetic analysis of functional networks and ontologies identified CDC7 as one of the relevant genes. Pharmacological CDC7 inhibition with XL413 markedly reduced cell viability and proliferation by induction of apoptosis in OSCC cell lines (Jin et al., 2018).

In order to screen for key osteosarcoma biomarkers, Liu et al. (Liu et al., 2016) systematically screened mRNA and proteins differently expressed, and CDC7 was found as part of a gene signature for osteosarcoma.

Ovarian carcinoma

CDC7 was a strong independent prognostic marker in epithelial ovarian carcinoma and CDC7 targeted inhibition leads to specific tumor cell death. In a cohort of 143 cases of ovarian cancer, increased levels of CDC7 protein were significantly associated with reduced tumor differentiation, advanced clinical stage, genomic instability, and accelerated cell cycle progression (Kulkarni et al., 2009). Moreover, CDC7 predicted disease-free survival, regardless of age, tumor grade and stage. CDC7 downregulation by siRNA in ovarian cancer cells (SKOV-3 and Caov-3) resulted in high levels of apoptosis (Kulkarni et al., 2009).

Pancreatic cancer

In a cohort of 73 pancreatic adenocarcinoma patients, including 24 controls, CDC7 was highly expressed in pancreatic adenocarcinoma compared to benign pancreatic tissue, as observed by immunohistochemistry (Huggett et al., 2016). CDC7 depletion using siRNA and PHA-76749, a CDC7 small molecule inhibitor, in pancreatic cancer cellular models (Capan-1 and PANC-1), resulted in marked apoptotic cell death. Using human pancreatic cell lines (Capan-1, BxPC3, and PANC-1), the preclinical efficacy of another CDC7 inhibitor, MSK-777, was reported (induction of cell cycle arrest in G1/S and apoptosis) (Skoura et al., 2013). Taken together, these results indicated that CDC7 is a potential target and may be used as a complementary diagnosis marker to predict responses in pancreatic adenocarcinoma.

Papillary thyroid carcinoma

Fluge et al. (Fluge et al., 2006) studied gene expression profile using cDNA microarray in papillary thyroid carcinoma samples, including 7 clinically aggressive carcinomas, 10 differentiated thyroid papillary carcinomas, and normal thyroid tissues, which were confirmed by RT-PCR, in situ hybridization and immunohistochemistry. Patients with aggressive and poorly differentiated thyroid carcinoma were specifically characterized by the marked positive regulation of several genes related to cell proliferation, including CDC7 (Fluge et al., 2006).

Salivary gland tumor

Jaafari-Ashkavandi et al. (Jaafari-Ashkavandi et al., 2019) reported high CDC7 expression in malignant salivary gland tumors compared to pleomorphic adenomas, and its positive correlation with tumor differentiation in samples from 15 cystic adenoid carcinomas, 12 mucoepidermoid carcinomas, 14 pleomorphic adenomas, and 5 normal salivary glands (total 46 patients and donors).

Uterine leiomyosarcoma

Barlin and colleagues (Barlin et al., 2015) compared the molecular profiles of 23 samples of uterine leiomyosarcoma (ULMS) and 29 samples of normal myometrium (NL) to identify clinically relevant molecular subtypes. Pathway analyses of genes differentially expressed between ULMS and NL samples identified over-representation of cell cycle regulation, DNA repair, and genomic integrity. External validation confirmed differential expression in 31 genes, with 84% overexpressed genes, including CDC7 and other cell cycle regulators (Barlin et al., 2015).