Chronic liver disease and primary liver cancer are a massive global problem, as the most prevalent form of primary liver cancer, hepatocellular carcinoma is a global pandemic with a significant increase in morbidity and mortality worldwide[1]. Recent epidemiology statistical data confirms that HCC represents the fourth leading cause of cancer-related death and ranks sixth in terms of new cases worldwide[2]. With a poor 5-year survival, liver cancer is the second most lethal tumor after pancreatic cancer[3].The tumorigenesis and development of HCC is a complex process involving multiple genes and factors[4] (Fig. 1). It has been reported that the mutation of p53[5], AKT/β-catenin[6], HFE[7], TSC1/2[8] and MBL[9] genes were frequently occurred in aggressive HCC. Meanwhile, the activation of these genes such as mTOR, PI3K, MAP kinase, STAT3, JAK were proved to be related with the progression of HCC[10–13]. Recently, metabolism reprogramming is also confirmed to behave distinctly in different periods of HCC[14–16].
The COpper Metabolism MURR1 Domain-containing (COMMD) family consists of ten members ranging from COMMD1 to COMMD10, which is characterized by a highly conservative COMM domain at the carboxyl terminal[17]. The COMMDs family members have been frequently reported to involve in human disease and cancers (Table 1). For example, the most researched COMMD1 induces apoptosis in human lung cancer cells by inhibition of NF-κB signaling[18, 19].COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion[20], and downregulation of COMMD1 promotes tumor development by modulating a positive feedback loop that amplifies inflammatory and stemness-associated properties of cancer cells. COMMD3/8 complex selectively recruited GRK6 and induced GRK6-mediated phosphorylation of the receptor and activation of β-arrestin-mediated signaling thus regulates immune response[21]. COMMD4 was defined as an anti-cancer therapeutic target and prognostic factor in non-small cell lung cancer[22]. COMMD5 acts as an adaptor protein to coordinate endosomal trafficking and plays an important role inEGFR transporting and activity in renal cell carcinoma[23]. COMMD6 may modulate the ubiquitination and degradation of NF-κB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumors[24]. COMMD9 participates in TFDP1/E2F1 activation and plays a critical role in non-small cell lung cancer[25]. COMMD10 may play a tumor suppressive role in renal clear cell carcinoma through the miR-590-3p-COMMD10-Cul2-RBX1-NF-κB/HIF/NRF2 pathway and regulate the chemotherapy resistance of various tumor cells to cisplatin[26, 27].In addition, the COMMDs family proteins also regulates plasma LDL Levels and attenuates atherosclerosis through forming COMMD/CCDC22/CCDC93 to stabilize the CCC complex in endosomal LDLR trafficking[28].
Table 1
Studies about COMMDs family proteins in different cancers and diseases
COMMD proteins
|
Study
|
Cancer and disease type
|
Regulated factors or pathway
|
Findings
|
COMMD1
|
Masso JR et al., 2013 [18]
|
Lung cancer
|
NF-κB pathway
|
COMMD1inhibited NF-κB activity and decreased the activation of antiapoptotic genes
|
Burstein et al., 2010 [20]
|
Pancreatic cancer, ovarian cancer, breast cancer
|
HIF−1α
|
COMMD1 prevented the dimerization of HIF−1α and HIF−1β and subsequent DNA binding and transcriptional activation
|
COMMD3/8
|
Suzuki et al., 2019 [21]
|
Humoral immune responses
|
β-arrestin-mediated signaling
|
COMMD3/8 complex selectively recruited GRK6 and induced GRK6-mediated phosphorylation of the receptor and activation of β-arresti-mediated signaling
|
COMMD4
|
Suraweera et al., 2020 [22]
|
Non-small cell lung cancer (NSCLC)
|
Not mentioned
|
COMMD4 expressed higher in NSCLC and promoted cell proliferation
|
COMMD5
|
Campion et al., 2018 [23]
|
Renal clear cell carcinoma (RCC)
|
EGFR
|
COMMD5 inhibited the growth of renal carcinoma cells by regulating EGFR trafficking
|
COMMD6
|
Yang et al., 2019 [24]
|
Liver cancer, lung cancer, etc.
|
NF-κB pathway
|
High expression of COMMD6 related with poor prognosis of tumors
|
COMMD7
|
Zheng et al., 2012 [38]
|
Hepatocellular carcinoma
|
NF-κB pathway
|
COMMD7 promoted the progression of HCC by negatively regulating NF-κB pathway
|
COMMD9
|
Zhan et al., 2017 [25]
|
NSCLC
|
TFDP1/E2F1
|
High expression of COMMD9 led to advanced NSCLC
|
COMMD10
|
Yang et al., 2017 [26]
|
RCC, Colorectal cancer
|
NF-κB pathway
|
COMMD10 inhibited the invasion and metastasis of colorectal cancer by promoting ubiquitination and degradation of NF-kB
|
As a key member of COMMDs family, COMMD7 consists of 200 amino acids and located on the 20th chromosome. Yet the bio-function of COMMD7 was rarely reported. Goodall et al, found that the SNP of COMMD7 may associated with platelet function of FC and PC[29].While Bajuna Rashid Salehe confirmed the association of the SNP rs6141803 of COMMD7 with cardiovascular diseases (CVDs) by interfering platelet function[30]. Our preliminary research revealed that COMMD7 was highly expressed in hepatocellular carcinoma and might play as an oncogenic role in HCC, and it may promote HCC through activating NF-κB signaling by regulating the expression of chemokine CXCL10.
In this study, we firstly launched the expression profile data and bioinformatics analysis of COMMD7 in HCC, combining with recent studies, we summarized the functional role of COMMD7 comprehensively, providing an overview for the latest research advances of it, which may help to direct targeted therapy of HCC.