Abstract
BackgroundDrug resistance frequently led to the failure of chemotherapy for malignant cancers, hence causing cancer relapse. Thus, understanding mechanism of drug resistance in cancer is vital to improve the treatment efficacy. Here, we aim to evaluate the association between SMAD4 expression and the drug resistance in cancers by performing a meta-analysis.MethodRelevant studies detecting SMAD4 expression in cancer patients treated with chemo-drugs up till December 2020 were systematically searched in four common scientific databases using selected keywords. The pooled hazard ratio (HR) was the ratio of hazard rate between SMAD4neg population vs SMAD4pos population. The HRs and risk ratios (RRs) with 95% confidence intervals (CIs) were used to explore the association between SMAD4 expression losses with drug resistance in cancers.ResultAfter an initial screening according to the inclusion and exclusion criteria, eleven studies were included in the meta-analysis. There were a total of 2092 patients from all the included studies in this analysis. Results obtained indicated that loss of SMAD4 expression was significantly correlated with drug resistance with pooled HRs (95% CI) of 1.23 (1.01–1.45), metastasis with pooled RRs (95% CI) of 1.10 (0.97–1.25) and recurrence with pooled RRs (95% CI) of 1.32 (1.06–1.64). In the subgroup analysis, cancer type, drug type, sample size and antibody brand did not affect the significance of association between loss of SMAD4 expression and drug resistance. In addition, there was no evidence of publication bias as suggested by Begg’s test.ConclusionFindings from our meta-analysis demonstrated that loss of SMAD4 expression was correlated with drug resistance, metastasis and recurrence. Therefore, SMAD4 expression could be potentially used as a molecular marker for cancer resistance.
Highlights
Drug resistance in cancers contributes to the failure of chemotherapy and the subsequent cancer relapse, causing the death of patients [1,2,3]
Findings from our meta-analysis demonstrated that loss of SMAD4 expression was correlated with drug resistance, metastasis and recurrence
It was well known that activated TGFβ induces epithelial-to-mesenchymal transition (EMT) that is often associated with cancer metastasis
Summary
Drug resistance in cancers contributes to the failure of chemotherapy and the subsequent cancer relapse, causing the death of patients [1,2,3]. TGFβ signaling pathway regulates multiple cellular processes, including cell proliferation, differentiation, apoptosis, and specification of developmental fate during embryogenesis as well as in mature tissues [6] The pathway ligands, such as TGFβs, BMPs and activins, bind to the TGFβ receptors to phosphorylate SMAD2 and SMAD3, forming a SMAD2/SMAD3 complex that subsequently interacts with SMAD4 to form a trimer complex, which is translocated into the nucleus to initiate the downstream target genes transcription [7]. Apart from this, a study by Michiko et al revealed that a high frequency of SMAD4 gene mutations existed in human colorectal cancers, showing that inactivation of SMAD4 is important during cancer progression [14]. This finding suggested the role of SMAD4 as a suppressor gene. We aim to evaluate the association between SMAD4 expression and the drug resistance in cancers by performing a meta-analysis
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