Research paperScreening and identification of haptoglobin showing its important role in pathophysiological process of gallbladder carcinoma
Introduction
Gallbladder cancer (GBC) has been much widespread in some regions in the world, especially in developing countries, despite it is a rare biliary tract malignancy in most western countries (Sharma et al., 2017). This cancer type has a relative low incidence rate, but GBC-associated mortality is unexpectedly higher than that in other cancer types (Liu et al., 2015). The main reason may be derived from lacking symptoms at initial stage that further leads to difficulties in timely treatment, and GBC is usually associated with late diagnosis and unsatisfactory treatment. The prognosis of advance patients is very poor with a 5-year survival rate of ~5% (Li et al., 2014), and the poor survival rate is derived from multiple reasons (Shu et al., 2014). The orphancancer is associated with multiple factors, mainly including key genetic and environmental factors, which further cause its poorly defined pathogenesis, development and progression (Misra et al., 2003). Hepatic invasion and metastatic progression may be a major reason of miserable prognosis of GBC due to lacking a serosallayer of gallbladder adjacent to the liver (Andia et al., 2008, Hundal and Shaffer, 2014). Currently, GBC has been a leading cause of cancer-related deaths worldwide, and it is quite urgent to develop novel and effective therapeutic targets to improve prognoses.
Similar to other cancer types, GBC is believed with a multifactorial disorder, including genetic alterations from multiple molecular levels (Wistuba et al., 2001, Rashid, 2002). For example, pathogenic mutations have been found in KRAS oncogene (Itoi et al., 1997, Masuhara et al., 2000, Rashid, 2002), and a well-known tumor suppressor gene, TP53 (Masuhara et al., 2000, Takada et al., 2002). Abnormal expression of oncogene c-erb-B2 can be found in dysplasia or adenomas (Kamel et al., 1993, Kim et al., 2001), and the c-erb-B2 gene may be a potential marker for a poor prognosis of GBC. Therapeutic targeting of EGFR/HER2 pathways can boost the anti-proliferative effect of gemcitabine (Pignochino et al., 2010), which provides a new insight for further treatment. CLIC1 gene may contribute to proliferation, migration, invasion and apoptosis of human gallbladder cancer cells (He et al., 2018), CA199 may be an efficient independent prognostic biomarker for postoperative patients (Xu et al., 2018), and this gene has been traditionally used for the diagnosis and prognosis of GBC (Wang et al., 2014). These studies have shown potential crucial genes in occurrence and development of GBC, and these genes may contribute to improving disease diagnosis and prognosis as potential effective therapeutic targets and increasing our understanding of biomarkers in predicting therapeutic responses.
Herein, we aimed to screen crucial genes in GBC, and further discussed the potential roles in tumorgenesis. A significantly up-regulated Haptoglobin (HP) was finally screened to perform in-depth analysis and further experimentally validate its potential biological roles in cell proliferation, migration and invasion. Although HP is mainly synthesized in liver, it showed various expression patterns in other different tissues, indicating its potential diverse functions associated with various tissues. Further experimental validation showed that HP contributed to cell proliferation, migration and invasion in tumorgenesis. Our study indicated that HP may be a crucial gene in GBC, especially for its association with cell migration and invasion, may contribute to pathophysiological process. Further studies should focus on its potential role in cancer treatment as a potential effective therapeutic target.
Section snippets
Data resources
To screen crucial molecules associated with GBC, we performed an integrative analysis of multiple datasets that were mainly retrieved from public data (Bamford et al., 2004, Tan et al., 2011, Sahasrabuddhe et al., 2014, Ma et al., 2016) (Table S1). Analyzed data also could be found in our developed database, GBCdb, http://tmliang.cn/gdcdatabase. Limited data in GBC were not enough to understand and screen the potential interactions and function implication of crucial genes, so further in-depth
Overview of expression landscape shows abnormal genes in GBC
To understand differentially expressed genes in GBC, we firstly screened abnormal gene expression profiles using published data (Table S1). A total of 174 deregulated genes were screened, including 127 down-regulated genes and 47 up-regulated genes (Fig. 1A). These genes were mainly distributed on some chromosomes, especially chr1, chr6, chr4 (Fig. 1A), implying relevant centralized distributions on specific chromosomes. We found that 100 deregulated genes were involved in KEGG pathways, 98
Discussion
Here, based on bioinformatic analysis in GBC and other cancer types, we finally screen and identify a potential crucial gene of HP. As an acute phase protein, it is mainly synthesized in liver, but HP is also detected with diverse enrichment levels in other tissues (Fig. 2). It may be associated with various cancers, and an increasing number of studies have shown that it is expressed in diverse cancer types, such as in epithelial ovarian cancers (Perumal et al., 2019), colorectal cancer (
Author contributions
L.G., X.L., and T.L. conceived and designed the study; M.L., Y.D., R.D., L.S., L.J., J.W. performed the data analysis and experiments; L.G. and T.L. wrote the paper with comments from other authors.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by National Natural Science Foundation of China [Nos. 61771251 and 81670570], the key project of social development in Jiangsu Province [No. BE2016773], the key research and development program of Jiangsu Province [No. BE2016789], the National Natural Science Foundation of Jiangsu [No. BK20171443], the Qinglan Project in Jiangsu Province, Sponsored by NUPTSF [No. NY220041], Achievements Incubation Project of Changzhou Institute of Innovation and Development of Nanjing
References (59)
Haptoglobin: old protein with new functions
Clin. Chim. Acta
(2011)- et al.
High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities
Cell
(2015) - et al.
Studies on the serum haptoglobin level in hemoglobinemia and its influence on renal excretion of hemoglobin
Blood
(1957) - et al.
Carcinoma of the gallbladder
Lancet Oncol.
(2003) - et al.
Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging
Blood
(2009) Cellular and molecular biology of biliary tract cancers
Surg. Oncol. Clin. N. Am.
(2002)- et al.
Identification of prosaposin and transgelin as potential biomarkers for gallbladder cancer using quantitative proteomics
Biochem. Biophys. Res. Commun.
(2014) - et al.
Smad proteins suppress CCAAT/enhancer-binding protein (C/EBP) beta- and STAT3-mediated transcriptional activation of the haptoglobin promoter
J. Biol. Chem.
(2001) - et al.
Identification of haptoglobin as a potential diagnostic biomarker of acute pulmonary embolism
Blood Coagul. Fibrinol.
(2018) - et al.
Predicting effective microRNA target sites in mammalian mRNAs
eLife
(2015)
Secretome identification of immune cell factors mediating metastatic cell homing
Sci. Rep.
Proteomic-based identification of haptoglobin-1 precursor as a novel circulating biomarker of ovarian cancer
Br. J. Cancer
Geographic variation of gallbladder cancer mortality and risk factors in Chile: a population-based ecologic study
Int. J. Cancer
The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website
Br. J. Cancer
Clusterin enhances AKT2-mediated motility of normal and cancer prostate cells through a PTEN and PHLPP1 circuit
J. Cell. Physiol.
Gene essentiality and synthetic lethality in haploid human cells
Science
Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis
J. Clin. Invest.
TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data
Nucl. Acids Res.
Identification of haptoglobin as a readout of rhGH therapy in GH deficiency
J. Clin. Endocrinol. Metab.
TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways
Acta Biochim. Biophys. Sin. (Shanghai)
A census of human cancer genes
Nat. Rev. Cancer
Haptoglobin or hemopexin therapy prevents acute adverse effects of resuscitation after prolonged storage of red cells
Circulation
Effect of CLIC1 gene silencing on proliferation, migration, invasion and apoptosis of human gallbladder cancer cells
J. Cell Mol. Med.
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Nat. Protoc.
Gallbladder cancer: epidemiology and outcome
Clin. Epidemiol.
Correlation of p53 protein expression with gene mutation in gall-bladder carcinomas
Pathol. Int.
p53 and c-erbB-2 protein expression in adenocarcinomas and epithelial dysplasias of the gall bladder
J. Pathol.
Expression of the c-erb-B2 and p53 protein in gallbladder carcinomas
Oncol. Rep.
Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway
Nat. Genet.
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These authors contributed equally to this work.