Background:Nearly 40% of breast cancer patients are ineligible for breast-conserving surgery. Immediate implant-based breast reconstruction is a preferred option for these patients. The most severe complication of this procedure is implant loss. Currently, there are no cytokines available to predict implant failure. To identify a drainage biomarker predicting implant loss and evaluate whether dexamethasone irrigation in high-risk cases is associated with reduced implant failure, we designed this study. Methods:A retrospective cohort study was conducted between December 2022 and March 2024, patients undergoing mastectomy with immediate implant-based reconstruction were recruited. We applied protein microarray to analyze cytokines in the drainage fluid from the implant pocket to identify cytokines associated with implant failure. Results:We initially selected 3 patients with implant failure and 3 with successful implant outcomes as the cohort for protein microarray analysis. Drainage fluid samples were collected and analyzed at 3 time points: 24 hours postoperatively, at drainage removal and at the onset of implant failure. This analysis identified intercellular adhesion molecule-1 (ICAM-1) as a candidate marker that meets the criteria for predicting implant failure. Subsequently, we validated ICAM-1's predictive potential in a separate cohort of breast cancer patients who underwent immediate implant-based breast reconstruction between December 2022 and March 2024. Our results demonstrated that ICAM-1 levels in drainage fluid at the time of drainage removal effectively predicted implant failure following immediate breast reconstruction for breast cancer. Additionally, a retrospective analysis revealed that intracavitary irrigation with dexamethasone significantly reduced ICAM-1 level in the drainage fluid and reversed impending implant failure. Conclusion:The data confirmed the potential of ICAM-1 as a predictive factor for breast implant failure. Intracavitary irrigation with dexamethasone was effective to prevent implant loss.

Lung adenocarcinoma, the most common histological subtype of non-small cell lung cancer, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Our team uncovers that lncRNA related to chemotherapy resistance in lung adenocarcinoma (lncCRLA) is preferentially expressed in lung adenocarcinoma cells with the mesenchymal phenotype. lncCRLA can not enhance chemotherapy resistance in lung adenocarcinoma due to its binding to RIPK1 in exosomes, which is released into intercellular media and transferred by exosomes from mesenchymal-like to epithelial-like cells. However, plasmatic lncCRLA corresponding to tissue lncCRLA functions as a preferred biomarker to reflect the response to chemotherapy and disease progression of lung adenocarcinoma. Through single-cell sequencing, RNA-Mutect technique and spatial transcriptomics, a handful of hybrid EMT cells with elevated lncCRLA are characterized as the origin of lung adenocarcinoma, which are indiscriminated from hybrid EMT cells by the in-depth sequencing. Plasmatic lncCRLA is properly predictive for the preinvasive lesion of lung adenocarcinoma that would evolve to invasive lesion. That notion is confirmed by a brand-new transgenic mouse model in which EMT is tracked by Cre and Dre system. Dasatinib is potential to hinder the spontaneous progression from preinvasive to invasive lesion of lung adenocarcinoma. Together, plasmatic lncCRLA is defined as a brand-new circulating biomarker to predict the occurrence and evolvement of lung adenocarcinoma, a light for early detection of lung adenocarcinoma.

Breast cancer is a prominent contributor to mortality associated with cancer in the female population on a global scale. The timely identification and precise categorization of breast cancer are of utmost importance in enhancing patient prognosis. Nevertheless, the task of precisely categorizing breast cancer based on ultrasound imaging continues to present difficulties, primarily due to the presence of dense breast tissues and their inherent heterogeneity. This study presents a unique approach for breast cancer categorization utilizing the wavelet based vision transformer network. To enhance the neural network’s receptive fields, we have incorporated the discrete wavelet transform (DWT) into the network input. This technique enables the capture of significant features in the frequency domain. The proposed model exhibits the capability to effectively capture intricate characteristics of breast tissue, hence enabling correct classification of breast cancer with a notable degree of precision and efficiency. We utilized two breast tumor ultrasound datasets, including 780 cases from Baheya hospital in Egypt and 267 patients from the UDIAT Diagnostic Centre of Sabadell in Spain. The findings of our study indicate that the proposed transformer network achieves exceptional performance in breast cancerclassification. With an AUC rate of 0.984 and 0.968 on both datasets, our approach surpasses conventional deep learning techniques, establishing itself as the leading method in this domain. This study signifies a noteworthy advancement in the diagnosis and categorization of breast cancer, showcasing the potential of the proposed transformer networks to enhance the efficacy of medical imaging analysis.

BackgroundThe combination of neoadjuvant chemotherapy and anti-angiogenesis therapy for patients with triple-negative breast cancer (TNBC) remains inadequately supported by evidence. We conducted a single-arm, open-label, multicenter, phase II trial to evaluate the efficacy and toxicity of anlotinib plus epirubicin and cyclophosphamide followed by paclitaxel in patients with IIB to IIIA stage TNBC.MethodsNewly diagnosed patients received epirubicin at 90 mg/m2 and cyclophosphamide at 600 mg/m2 followed by docetaxel at 100 mg/m2 (21 days per cycle; total of 4 cycles), along with oral anlotinib (12 mg qd, d1-14; 21 days per cycle; total of 4 cycles). Subsequently, patients underwent surgery. The primary endpoint of this study was pathologic complete response (pCR).Results: Among the 34 included patients, the median age was 46.5 years (range: 27-72); all were female. Pathological assessment revealed that 17 patients achieved RCB 0 response, which is currently defined as pathologic complete response; 3 patients achieved RCB 1; 12 patients achieved RCB 2; and 1 patient achieved RCB 3. The probability of a grade 3 adverse reaction was 17.6%, and no grade 4 adverse reactions occurred. The most common hematological adverse reaction was leukopenia (13/34, 38.2%), of which 5.9% (2/34) were grade 3. The most common non-hematological adverse reactions were oral mucositis (16/34, 58.8%), fatigue (50.0%), hand-foot syndrome (50.0%), hypertension (44.1%), bleeding (44.1%), and alopecia (32.4%).ConclusionThe combination of anlotinib and EC-T chemotherapy demonstrated tolerable side effects in the neoadjuvant treatment of early TNBC. pCR was higher than what has been reported in previous clinical studies of chemotherapy alone. This study provides additional rationale for using anlotinib plus docetaxel-epirubicin-based chemotherapy regimen in patients with early-stage TNBCs.

Background: Existing research shows inducing ferroptosis can improve the effectiveness of tumor treatment. Glutathione peroxidase 4 (GPX4) is a ferroptosis inhibitor. Solute carrier family 7, membrane 11 (SLC7A11) plays a key role in glutathione homeostasis, which is important for protecting cells from oxidative stress. (3-catenin is the key protein the Wnt/(3-catenin signaling pathway. The purpose of this study was to investigate the expression of SLC7A11 and GPX4 in colorectal cancer (CRC) and their relationship with (3-catenin and to analyze the association of these two factors with several clinicopathological features and patient survival. Methods: This study retrospectively collected paraffin-embedded tissue samples from 120 CRC patients, who received surgical resection between 2017 and 2018. We examined the patterns of expression of SLC7A11, GPX4 and (3-catenin by using immunohistochemistry. Analyzing the relationships between SLC7A11, GPX4, (3-catenin and clinical pathological parameters and their relationships with overall survival (OS). Results: Expression of SLC7A11 and GPX4 were high expression in 60.83% and 64.17% among the patients, respectively, and were higher than those in normal tissue. SLC7A11, GPX4 and (3-catenin were positively correlated with each other (P<0.05). Expression of SLC7A11 and GPX4 significantly correlates with tumor stage and lymph node metastasis (P < 0.05). The (3-catenin was related to lymph node metastasis, TNM stage and tumor grade. Kaplan-Meier analysis showed that patient's OS in the SLC7A11 and GPX4 were reduced (P<0.05). Univariate and multivariate analyses showed that SLC7A11 and GPX4 were independent risk factors for CRC prognosis. Conclusion: SLC7A11 and GPX4 overexpression is associated with (3-catenin and poor prognosis and may be important for predicting CRC invasion, metastasis, and prognosis.

Background:As one of the most widely used anti-diabetic drugs for type II diabetes, metformin has been shown to exhibit anti-cancer activity in recent years. Epidermal growth factor (EGF) and its receptor, EGFR, play important roles in cancer metastasis in various tumors, including breast cancer. Epithelial-mesenchymal transition (EMT) is a critical process for cancer invasion and metastasis. In this study, we use EGF as a metastatic inducer to investigate the effect of metformin on cancer cell migration, invasion and EMT.Methods:Human breast cancer MCF-7 cells were exposed to EGF with or without metformin or N-acetyl cysteine (NAC). The effects of metformin on breast cancer cell proliferation were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The production of reactive oxygen species (ROS) was tested using 2,7-dichlorodihydrofluorecein diacetate (DCFH-DA). The migratory and invasive abilities of tumor cells were analyzed using wound healing assay and transwell invasion assay, respectively. The expressions of E-cadherin, N-cadherin and Snail were tested using real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting at mRNA and protein levels. The activation of protein kinase B (Akt) and nuclear factor kappa B (NF-κB) were measured by western blotting.Results:Our results showed that metformin inhibited breast cancer cell proliferation in a dose-dependent manner with or without EGF. EGF-induced alterations in cell morphology that are characteristic of EMT were reversed by metformin. Metformin also inhibited the EGF-modulated expression of E-cadherin, N-cadherin and Snail and further suppressed cell invasion and migration. In addition, metformin suppressed EGF-induced phosphorylation of Akt and NF-κB. ROS is involved in EGF-induced cancer invasion and activation of phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB pathway.Conclusion:Taken together, these data indicate that metformin suppresses EGF-induced breast cancer cell migration, invasion and EMT through the inhibition of the PI3K/Akt/NF-κB pathway. These results provide a novel mechanism to explain the role of metformin as a potent anti-metastatic agent in breast cancer cells.

Hypoxia and its induced vasculogenic mimicry (VM) formation, which both closely related with stem-like side population (SP) cells, are the main culprits leading to tumor invasion and metastasis. Sinomenine exhibits excellent anticancer activity in breast cancer, but whether and how it affects hypoxia-triggered VM formation in breast cancer SP cells remains unclear. In this study, breast cancer SP cells were sorted from MDA-MB-231 cells and cultured with sinomenine under hypoxic conditions. Sinomenine obviously repressed the migration and VM formation of breast cancer SP cells. Through downregulating SIAH2 and HIF-1α, sinomenine can inhibit epithelial-mesenchymal transition process of breast cancer SP cells. SIAH2 was identified as a target of miR-340-5p and was downregulated by it, and sinomenine can upregulate miR-340-5p. Hypoxia-induced downregulation of miR-340-5p and activation of SIAH2/HIF-1α pathway can be both counteracted by the sinomenine. Moreover, miR-340-5p inhibition and SIAH2 overexpression can partly counteract the anticancer effects of sinomenine. Taken together, sinomenine inhibits hypoxia-caused VM formation and metastasis of breast cancer SP cells by regulating the miR-340-5p/SIAH2 axis.

Pancreatic cancer (PC) is one of the most lethal diseases, with a 5-year survival rate of <9%. Perineural invasion (PNI) is a common pathological hallmark of PC and is correlated with a poor prognosis in this disease. Hyperglycemia has been shown to promote the invasion and migration of PC cells; however, the effect of hyperglycemia on the PNI of PC and its underlying mechanism remains unclear. In the present study, Western blotting was utilized to detect the expression of hypoxia inducible factor 1α (HIF1α) and nerve growth factor (NGF). Transwell and wound-healing assays were performed to detect the influence of hyperglycemia on the invasion and migration ability of PC cells. An in vitro PC-dorsal root ganglion (DRG) co-culture system and an in vivo PNI sciatic nerve-infiltrating tumor model were used to evaluate the severity of PNI in hyperglycemic conditions. In the results, hyperglycemia promoted the invasion/migration ability and elevated the expression of NGF in PC by upregulating HIF1α. Moreover, in vitro short-term hyperglycemia caused little damage on the DRG axons and accelerated both the PNI of the PC and the outgrowth of the DRGs by increasing the expression of NGF via activation of HIF1α. Indeed, in vivo long-term hyperglycemia promoted the infiltration and growth of PC, and then disrupted the function of the sciatic nerve in a HIF1α-dependent manner. In conclusion, a high-glucose microenvironment promotes PNI of PC via activation of HIF1α.

Sinomenine is an alkaloid derived from Chinese medicinal plant Sinomenium acutum. Our previous studies suggested that sinomenine can inhibit the metastasis of breast cancer. However, whether sinomenine can inhibit the metastasis characteristics of breast cancer side population (SP) cells is still unknown. In present study, we isolated the side population (SP) cells from MDA-MB-231 cells by fluorescence-activated cell sorting (FACS). MDA-MB-231 SP cells were treated with different concentrations of sinomenine at the absence or presence of hypoxia, and cell viability were measured by CCK-8 assay. The transwell invasive assay were conducted to assess of the effect of sinomenine on the invasion of hypoxic MDA-MB-231 SP cells. The protein expression was detected by Western blot assay. Sinomenine inhibited the cell viability and invasion of hypoxic MDA-MB-231 SP cells. Western blot assay results showed that the upregulation of MMP-2 and MMP-9 by hypoxia was inversed by sinomenine. Additionally, it was found that sinomenine suppressed the activation of PI3K/Akt/mTOR pathway under hypoxia in MDA-MB-231 SP cells. Moreover, the inhibiton of sinomenine on metastasis of hypoxic MDA-MB-231SP cells and PI3K/Akt/mTOR pathway could be rescued by PI3K activator IGF-1. Our study suggested that sinomenine inhibits invasion of breast cancer SP cells under hypoxia through PI3K/Akt/mTOR pathway.

c-Src and the epidermal growth factor receptor (EGFR) are key apical kinases that govern cell responses to microenvironmental cues. How c-Src affects EGFR-related signaling and targeted therapy remains elusive. Initially, caspase-8 phosphorylated at tyrosine 380 by c-Src predominantly enhancing c-Src activation to facilitate metastasis through attaining epithelial-mesenchymal transition (EMT) phenotype in lung adenocarcinoma. Mechanistically, the linkage of c-Src SH2 domain with phosphotyrosine 380 of caspase-8 and SH3 domain with “PDEP” motif of caspase-8 overactivates c-Src as compared with other c-Src-partner proteins. c-Src is incapable of triggering EGFR-related signaling. This is reflected by the levels of phosphotyrosine 1068, 1086, and 1145, which have no impact on c-Src activation. Tyrosine kinase inhibitors (TKIs) suppress EGFR-related signaling to yield cell deaths of lung adenocarcinoma by both necroptosis and intrinsic apoptosis. Given that c-Src activation is frequent in lung adenocarcinoma, blocking c-Src activation through dasatinib can seal the survival-signaling-related phosphotyrosines of EGFR by its SH2 domain, which in turn increases the antitumor activity of TKIs in EGFR-mutant lung adenocarcinoma. Collectively, c-Src inactivation by dasatinib administration sensitizes EGFR-mutant lung adenocarcinoma to TKIs.

The specific function of microRNA-552 (miR-552) has been investigated in several malignancies, except gastric cancer (GC). Therefore, this study was performed to determine the role of miR-552 in GC.GC tissues and adjacent non-tumor tissues were collected to determine the expressions of miR-552. Quantitative real-time polymerase chain reaction assays (RT-qPCR) and Western blot analysis were carried out to measure expression levels. The regulatory mechanism of miR-552 was explored by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) MTT Assay, and Transwell assays. The binding site between miR-552 and FOXO1 was verified by dual-luciferase reporter assays. Upregulation of miR-552 expression was detected and associated with worse clinical outcomes in GC. Furthermore, high miR-552 expression predicted poor prognosis in GC patients. Functionally, upregulation of miR-552 promoted cell viability, metastasis, epithelial-mesenchymal transition (EMT), and phosphatidylinositol 3-kinase and protein kinase B (PI3K/AKT) pathway in GC. In addition, miR-552 was confirmed to target forkhead box O1 (FOXO1) directly and inversely regulate its expression in GC. Upregulation of FOXO1 reversed the carcinogenesis of miR-552 in GC. In conclusion, miR-552 serves as a tumor promoter in GC through targeting FOXO1 and regulating EMT and PI3K/AKT pathway.

EMT confers increased metastatic potential and the resistance to chemotherapies to cancer cells. However, the precise mechanisms of EMT-related chemotherapy resistance remain unclear. c-Src-mediated caspase 8 phosphorylation essential for EMT in lung adenocarcinoma cell lines preferentially occurs in cells with the mesenchymal phenotype, resulting in chemoresistance to cisplatin plus paclitaxel in patients with resectable lung adenocarcinoma and a significantly worse 5-year PFS. Cisplatin killed lung adenocarcinoma cells regardless of caspase 8. Paclitaxel-triggered necroptosis in lung adenocarcinoma cells was dependent on the phosphorylation or deficiency of caspase 8, during which FADD interacted with RIPK1 to activate the RIPK1/RIPK3/MLKL signaling axis. Accompanied with c-Src-mediated caspase 8 phosphorylation to trigger EMT, a novel lncRNA named lncCRLA was markedly upregulated and inhibited RIPK1-induced necroptosis by impairing RIPK1RIPK3 interaction via binding to the intermediate domain of RIPK1. Dasatinib mitigated c-Src-mediated phosphorylation of caspase 8-induced EMT and enhanced necroptosis in mesenchymal-like lung adenocarcinoma cells treated with paclitaxel, while c-FLIP knockdown predominantly sensitized the mesenchymal-like lung adenocarcinoma cells to paclitaxel+dasatinib. c-Srccaspase 8 interaction initiates EMT and chemoresistance via caspase 8 phosphorylation and lncCRLA expression, to which the dasatinib/paclitaxel liposome+siFLIP regimen was lethal.

BACKGROUND:The present study aimed to review the use of hypoglycemic drugs and clinicopathological data in breast cancer patients with type 2 diabetes mellitus (T2DM), and to investigate the effect of metformin on the clinicopathological features of breast cancer in patient with T2DM.METHODS:Eighty-nine patients with breast cancer hospitalized in the Second Affiliated Hospital of Xi'an Jiaotong University from January 2012 to December 2014 were included. Thirty-three patients were on metformin (metformin group) and 56 patients were on control group. Streptavidin-peroxidase (SP) method was used to quantify protein expression of molecular markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2)), molecular markers of proliferation (Ki-67 and epidermal growth factor receptor (EGFR)) and epithelial-mesenchymal transition (EMT) molecular markers (matrix metalloproteinase-2 (MMP-2), E-cadherin and downstream N-cadherin). Fluorescence in situ hybridization was used to detect HER-2 (+ and ++).RESULTS:The rate of lymph node metastasis and the level of Ki-67/MMP-2 in the metformin group were significantly lower than those in the control group (P < 0.05). The ratio of luminal pattern in metformin group was higher than that in the control group (P < 0.05). However, there were no differences in the parameters of age, duration of diabetes, body mass index, tumor size, histological grade of cancer and clinical pathological features between the two groups. No significant difference was observed in the expressions of ER, PR, HER-2, EGFR, E-cadherin, N-cadherin and the recurrence rate between two groups.CONCLUSIONS:Metformin is associated with luminal breast cancer and can inhibit breast cancer invasion and metastasis in some cases. It may be associated with EMT and is beneficial to the prognosis of breast cancer.

Herein, a novel phototheranostic nanocomplex that is self-assembled from bovine serum albumin (BSA) and indocyanine green (ICG) is developed for enhanced near-infrared (NIR) fluorescence imaging, which benefits the guidance on in vivo cancer photothermal therapy (PTT). The study confirms that the binding of ICG with the bind sits on the albumin will result in improved hydrolytic stability and high photoluminescence quantum yield (PLQY). The ICG loading ratio in the nanocomplex is optimized and confirms the loading ratio of 0.5% ICG to be the optimal content. The optimized ICG-BSA nanocomplex (ICG-BSA NC) possesses a higher PLQY of 16.8% than that of free ICG (2.7%). The high PLQY and efficient passive targeting ability of ICG-BSA NC help improve its in vivo tumor accumulation and NIR fluorescence imaging significantly. Under laser irradiation, efficient PTT with obvious tumor growth suppression on a triple negative breast tumor model can be observed in the ICG-BSA NC treated group.

Currently, the number of negative lymph nodes (NLNs) has been paid increasing attention and is considered a prognostic indicator in diverse cancers. Therefore, it is necessary to explore the association between number of NLNs and prognosis in esophageal cancer (EC) patients. Our data were obtained from the Surveillance, Epidemiology, and End Results 18 database. The X-tile plot was used to determine the optimal cut-off value of the number of NLNs, and propensity score matching (PSM) was performed according to the results of the X-tile plot. A total of 4777 patients were eligible, and 882 pairs of patients were included after PSM. The result of the X-tile plot revealed an optimal cut-off value of three NLNs. Multivariate Cox regression analysis revealed better EC-specific survival (ECSS) in patients with more than three NLNs (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.59–0.77; p < 0.001) compared with patients with three or fewer NLNs. A subgroup analysis revealed better ECSS in patients with more than three NLNs with one to two (HR 0.57, 95% CI 0.46–0.71; p < 0.001) or three to six (HR 0.68, 95% CI 0.50–0.92; p = 0.012) positive lymph nodes (PLNs). More than three NLNs is associated with better survival in EC patients, especially when the number of PLNs is one to two or three to six. We confirm that the combination of the number of NLNs and number of PLNs can provide better prognostic guidance for EC.

The dysregulation of long non-coding RNA (lncRNA) DLX6-AS1 has been identified to be involved in the development of several cancers, but its functional role and the underlying mechanism of DLX6-AS1 in breast cancer (BC) remains unknown. In the current study, the expression of DLX6-AS1 in the BC tissue samples was evaluated and the correlation between DLX6-AS1 expression and clinicopathological parameters were also analyzed. We found that DLX6-AS1 expression was much higher in tumor tissues than that in adjacent normal tissues and was positively associated with poor prognosis in BC patients. DLX6-AS1 knockdown significantly suppressed BC cell proliferation, invasion, migration, and promoted apoptosis. Moreover, luciferase reporter assay validated that DLX6-AS1 acted as an endogenous sponge to miR-505-3p and negatively regulated its expression. Additionally, miR-505-3p inhibited runt-related transcription factor 2 (RUNX2) expression by directly bind to its 3'-untranslated region (3'-UTR) and overexpression of RUNX2 partially reversed the effect of miR-505-3p mimics on BC cell proliferation and invasion. Furthermore, in BC tissues, miR-505-3p expression level was inversely associated with DLX6-AS1 and RUNX2, respectively. In conclusion, these findings demonstrated that DLX6-AS1 functioned as an oncogenic role that promoted BC proliferation and invasion through miR-505-3p/RUNX2 axis, which might serve as a potential therapeutic target for BC treatment.

The prostate-specific G protein-coupled receptor (PSGR) is a class A G protein-coupled receptor (GPCR) that is specifically expressed in prostate epithelial cells, and its expression has been linked to prostate cancer (PCa) progression. Here, we show that activation of PSGR with its ligand β-ionone, an end-ring analog of β-carotenoid, can suppress PCa cell growth both in vitro and in vivo model. Dissection of the mechanism underlying this relationship reveals that activation of PSGR by β-ionone suppresses AR nuclear translocation via phosphorylation of AR at residue Ser650 by p38 and JNK, which leads to the suppression of AR transactivation, further suppressing PCa cell growth. Overall, we link a cancer cell-specific GPCR with the nuclear AR and show that targeting PSGR can provide us a new target to combat PCa better.

OBJECTIVE:Although DNA-mismatch-repair-deficient (dMMR) status and aberrant expression of miRNAs are both critically implicated in the pathogenesis of resistance to 5-fluorouracil (5-FU) in colorectal cancer (CRC), whether these two factors regulate tumor response to 5-FU in a coordinated manner remains unknown. This study is designed to elucidate whether changes in miR-552 expression levels correlate to 5-FU-based chemoresistance in CRC, and to further identify the putative targets of miR-552 using multiple approaches.METHODS:miR-552 expression was assessed in 5-FU-resistant CRC tissues and cells using real-time PCR. Effects of miR-552 dysregulation on 5-FU resistance in CRC cells were determined by measuring cell viability, apoptosis and in vivo oncogenic capacity. Finally, we studied the posttranscriptional regulation of SMAD2 by miR-552 using multiple approaches including luciferase reporter assay, site-directed mutagenesis and transient/stable transfection, at molecular and functional levels.RESULTS:Expression of miR-552 was significantly downregulated in 5-FU-resistant CRC tissues and cells, and this downregulation, regulated by dMMR, was associated with poor postchemotherapy prognosis. Functionally, forced expression of miR-552 exhibited a proapoptotic effect and attenuated 5-FU resistance, whereas inhibition of miR-552 expression potentiated 5-FU resistance in CRC cells. Mechanically, miR-552 directly targeted the 3'-UTR of SMAD2, and stable ablation of SMAD2 neutralized the promoting effects of miR-552 deficiency-induced 5-FU resistance.CONCLUSIONS:Overall, our findings have revealed a critical role of miR-552/SMAD2 cascade in modulating cellular response to 5-FU chemotherapy. miR-552 may act as an efficient mechanistic link synchronizing dMMR and 5-FU resistance in CRC.