First Case of a Dominant De Novo SEC23A Mutation with Neurological and Psychiatric Features: New Insights into Cranio-Lenticulo-Sutural Dysplasia with Literature Review.

Cranio-lenticulo-sutural dysplasia (CLSD, OMIM #607812) is a rare genetic condition characterized by late-closing fontanels, skeletal defects, dysmorphisms, and congenital cataracts that are caused by bi-allelic or monoallelic variants in the SEC23A gene. Autosomal recessive inheritance (AR-CLSD) has been extensively documented in several cases with homozygous or compound heterozygous variants in SEC23A, whereas autosomal dominant inheritance (AD-CLSD) involving heterozygous inherited variants has been reported just in three patients. The SEC23A gene encodes for one of the main components of a protein coat complex known as coat-protein-complex II (COPII), responsible for the generation of the envelope of the vesicles exported from the endoplasmic reticulum (ER) toward the Golgi complex (GC). AR-CLSD and AD-CLSD exhibit common features, although each form also presents distinctive and peculiar characteristics. Herein, we describe a rare case of a 10-year-old boy with a history of an anterior fontanel that closed only at the age of 9. The patient presents with short proportionate stature, low weight, and neurological impairment, including intellectual disability, global developmental delay, abnormal coordination, dystonia, and motor tics, along with dysmorphisms such as a wide anterior fontanel, hypertelorism, frontal bossing, broad nose, high-arched palate, and micrognathia. Trio clinical exome was performed, and a de novo heterozygous missense variant in SEC23A (p.Arg716Cys) was identified. This is the first reported case of CLSD caused by a de novo heterozygous missense variant in SEC23A presenting specific neurological manifestations never described before. For the first time, we have conducted a comprehensive phenotype-genotype correlation using data from our patient and the eight most well-documented cases in the literature. Our work has allowed us to identify the main specific and characteristic signs of both forms of CLSD (AR-CLSD, AD CLSD), offering valuable insights that can guide physicians in the diagnostic process. Notably, detailed descriptions of neurological features such as intellectual disability, global developmental delay, and motor impairment have not been documented before. Furthermore, our literature overview is crucial in the current landscape of CLSD due to the absence of guidelines for the clinical diagnosis and proper follow-up of these patients, especially during childhood.

Novel compound heterozygous variants of the SEC23A gene in a Chinese family with cranio-lenticulo-sutural dysplasia based on data from a large cohort of congenital cataract patients.

BACKGROUND: Cranio-lenticulo-sutural dysplasia (CLSD) is a rare dysmorphic syndrome characterized by skeletal dysmorphism, late-closing fontanels, and cataracts. CLSD is caused by mutations in the SEC23A gene (OMIM# 607812) and can be inherited in either an autosomal dominant or autosomal recessive pattern. To date, only four mutations have been reported to cause CLSD. This study aims to identify the disease-causing variants in a large cohort of congenital cataract patients, to expand the genotypic and phenotypic spectrum of CLSD, and to confirm the association between SEC23A and autosomal recessive CLSD (ARCLSD). METHODS: We collected detailed medical records and performed comprehensive ocular examinations and whole-exome sequencing (WES) on 115 patients with congenital cataracts. After suspecting that a patient may have CLSD based on the sequencing results, we proceeded to conduct transmission electron microscopy (TEM) on the cultured skin fibroblasts. The clinical validity of the reported gene-disease relationships for the gene and the disease was evaluated using the ClinGen gene curation framework. RESULTS: Two novel compound heterozygous variants (c.710A > C p.Asp237Ala, c.1946T > C p.Leu649Pro) of the SEC23A gene, classified as variant of uncertain significance, were identified in the proband with skeletal, cardiac, ocular, and hearing defects. The observation of typical distended endoplasmic reticulum cisternae further supported the diagnosis of CLSD. Application of the ClinGen gene curation framework confirmed the association between SEC23A and ARCLSD. CONCLUSION: This study expands the genotypic and phenotypic spectrum of CLSD, proposes TEM as a supplemental diagnostic method, and indicates that congenital cataracts are a typical sign of ARCLSD.

SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop.

BACKGROUND: Sec23 homolog A (SEC23A), a core component of coat protein complex II (COPII), has been reported to be involved in several cancers. However, the role of SEC23A in gastric cancer remains unclear. METHODS: The expression of SEC23A in gastric cancer was analyzed by using qRT-PCR, western blotting and IHC staining. The role of SEC23A in ER stress resistance was explored by functional experiments in vitro and vivo. The occupation of STAT3 on the SEC23A promoter region was verified by luciferase reporter plasmids and CHIP assay. The interaction between SEC23A and ANXA2 was identified by Co-IP and mass spectrometry analysis. RESULTS: We demonstrated that SEC23A was upregulated in gastric cancer and predicted poor prognosis in patients with gastric cancer. Mechanistically, SEC23A was transcriptional upregulated by ER stress-induced pY705-STAT3. Highly expressed SEC23A promoted autophagy by regulating the cellular localization of ANXA2. The SEC23A-ANXA2-autophay axis, in turn, protected gastric cancer cells from ER stress-induced apoptosis. Furthermore, we identified SEC23A attenuated 5-FU therapeutic effectiveness in gastric cancer cells through autophagy-mediated ER stress relief. CONCLUSION: We reveal an ER stress-SEC23A-autophagy negative feedback loop that enhances the ability of gastric cancer cells to resist the adverse survival environments. These results identify SEC23A as a promising molecular target for potential therapeutic intervention and prognostic prediction in patients with gastric cancer.

Synergistic inhibition of NUDT21 by secretory S100A11 and exosomal miR-487a-5p promotes melanoma oligo- to poly-metastatic progression.

Although early diagnosis and therapeutic advances have transformed the living quality and outcome of cancer patients, the poor prognosis for metastatic patients has not been significantly improved. Mechanisms underlying the complexity of metastasis cannot be simply determined by the straightforward 'cause-and-effect relationships'. We have developed a 'dry-lab-driven knowledge discovery and wet-lab validation' approach to embrace the complexity of cancer and metastasis. We have revealed for the first time that polymetastatic (POL) melanoma cells can utilize both the secretory protein pathway (S100A11-Sec23a) and the exosomal crosstalk (miR-487a-5p) to transfer their 'polymetastatic competency' to the oligometastatic (OL) melanoma cells, via synergistic co-targeting of the tumor-suppressor Nudt21. The downstream deregulated glycolysis was verified to regulate metastatic colonization efficiency. Further, two gene sets conferring independent prognosis in melanoma were identified, which have the potential for clinical translation and merit future clinical validation.

Increased SEC23A Expression Correlates with Poor Prognosis and Immune Infiltration in Stomach Adenocarcinoma.

BACKGROUND: Previous studies have described that the SEC23A gene is involved in the occurrence and development of various tumor entities. However, little is known about its expression and relevance in stomach adenocarcinoma (STAD). The aim of this study was to bioinformatically analyze the role of SEC23A in STAD, followed by patient tissue sample analyses. MATERIALS AND METHODS: SEC23A expression levels in STAD and normal gastric tissues were analyzed in the Cancer Genome Atlas and Gene Expression Omnibus databases; results were verified in fresh clinical STAD specimens on both gene and protein expression levels. SEC23A expression correlated with survival parameters by Kaplan-Meier and multivariate Cox regression analyses. The top genes co-expressed with SEC23A were identified by gene set enrichment analysis (GSEA) using the clusterProfiler package in R. Furthermore, the R package (immunedeconv), integrating the CIBERSORT algorithm, was used to estimate immune cell infiltration levels in STAD. RESULTS: SEC23A gene and sec23a protein expression were both significantly upregulated in STAD, and this correlated with the pT stage. Moreover, high SEC23A expression was associated with poor disease-free and overall survival of STAD patients. Cox analyses revealed that besides age and pathologic stage, SEC23A expression is an independent risk factor for STAD. GSEA indicated that SEC23A was positively associated with ECM-related pathways. In the CIBERSORT analysis, the level of SEC23A negatively correlated with various infiltrating immune cell subsets, including follicular helper T cells, Tregs, activated NK cells and myeloid dendritic cells. Finally, the expression levels of immune checkpoint-related genes, including HAVCR2 and PDCD1LG2, were significantly increased in the high SEC23A expression group. CONCLUSIONS: We observed the significantly upregulated expression of SEC23A in STAD, an association with disease progression, patients' prognosis and infiltrating immune cell subsets. Thus, we propose SEC23A as an independent prognostic factor with a putative role in immune response regulation in STAD.

Low TINAGL1 expression is a marker for poor prognosis in breast cancer.

PURPOSE: Tubulointerstitial nephritis antigen-like 1 (TINAGL1) was reported to suppress tumor metastasis and growth in triple-negative (TN) breast cancer. We aimed to determine the associations of TINAGL1 expression with clinicopathological factors and prognosis in breast cancer patients with long-term follow-up. METHODS: A total of 599 consecutive primary invasive breast cancer patients with available tissue specimens from surgery in our hospital were included in the study. TINAGL1 mRNA expression was examined in all 599 tissue specimens using a TaqMan real-time PCR system. TINAGL1 protein expression was further examined in 299 patients with available tissue specimens for immunohistochemical staining. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: The median follow-up period was 12.0 years. In the total patients, low TINAGL1 mRNA expression was associated with significantly shorter disease-free survival (DFS) and overall survival than high expression (P = 0.003 and P = 0.01, respectively). Furthermore, hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer patients with low TINAGL1 mRNA expression had a worse prognosis. Multivariate analysis identified low TINAGL1 mRNA expression, combined with lymph node positivity, as an independent poor prognostic factor for DFS in invasive breast cancer patients (HR 1.41; 95% CI 1.02-1.96; P = 0.036). TINAGL1 mRNA expression also varied with menopausal status, with low TINAGL1 mRNA expression being positively associated with poor prognosis in premenopausal patients, but not in postmenopausal patients. CONCLUSION: Our findings demonstrate that TINAGL1 may be a promising candidate biomarker and therapeutic target in breast cancer patients.

Sec23a inhibits the self-renewal of melanoma cancer stem cells via inactivation of ER-phagy.

BACKGROUND: The genesis and developments of solid tumors, analogous to the renewal of healthy tissues, are driven by a subpopulation of dedicated stem cells, known as cancer stem cells (CSCs), that exhibit long-term clonal repopulation and self-renewal capacity. CSCs may regulate tumor initiation, growth, dormancy, metastasis, recurrence and chemoresistance. While autophagy has been proposed as a regulator of the stemness of CSCs, the underlying mechanisms requires further elucidation. METHODS: The CSC component in human melanoma cell lines M14 and A375 was isolated and purified by repetitive enrichments for cells that consistently display anchorage-independent spheroid growth. The stemness properties of the CSCs were confirmed in vitro by the expressions of stemness marker genes, the single-cell cloning assay and the serial spheroid formation assay. Subcutaneous tumor transplantation assay in BALB/c nude mice was performed to test the stemness properties of the CSCs in vivo. The autophagic activity was confirmed by the protein level of LC3 and P62, mRFP-LC3B punta and cytoplasmic accumulation of autolysosomes. The morphology of ER was detected with transmission electron microscopy. RESULTS: In the present study, by employing stable CSC cell lines derived from human melanoma cell lines M14 and A375, we show for the first time that Sec23a inhibits the self-renewal of melanoma CSCs via inactivation of ER-phagy. Mechanistically, inhibition of Sec23a reduces ER stress and consequently FAM134B-induced ER-phagy. Furthermore, TCGA data mining and analysis show that Sec23a is a favorable diagnostic and prognostic marker for human skin cutaneous melanoma. CONCLUSION: This study has elucidated a new mechanism underlying the regulation of autophagy on stemness, i.e. CSCs can exploit the SEC23A/ER-stress/FAM134B/ER-phagy axis for the self-renewal. These observations provide new ideas for exploration of the regulatory network of CSC self-renewal to develop CSCs-based therapy strategies for malignant tumors. Video Abstract.

MiR-29b-3p Inhibits the Inflammation Injury in Human Umbilical Vein Endothelial Cells by Regulating SEC23A.

This study aims to investigate the effects of miR-29b-3p on the inflammation injury of human umbilical vein endothelial cells (HUVECs) induced by lipopolysaccharide (LPS) and explore the underlying mechanisms. The effects of different concentrations of LPS (0, 1, 5 and 10 µg/mL) on inflammation injury in HUVECs are detected by ELISA, CCK-8, EdU, flow cytometry and western blot analyses to determine the optimal stimulus concentration. After stimulating HUVECs with 10 µg/mL LPS, the expression levels of miR-29b-3p are detected, and the effects of miR-29b-3p on inflammation injury are detected by ELISA, CCK-8, EdU, flow cytometry and western blot analyses. Bioinformatic analysis, luciferase reporter assay and confirmatory experiments are applied to identify the target gene bound with miR-29b-3p. Rescue experiments have verified the roles of miR-29b-3p and the target gene in inflammation injury. We found that pro-inflammatory factor was increased, apoptosis was promoted, and cell proliferation was inhibited after the treatment of LPS in HUVECs. Overexpression of miR-29b-3p inhibited LPS-induced inflammatory response and apoptosis while promoting proliferation in HUVECs. Besides, bioinformatics analysis indicated that SEC23A was the target gene of miR-29b-3p and the confirmatory experiments showed that SEC23A was negatively correlated with miR-29b-3p and positively correlated with LPS concentration. Rescue experiments revealed that overexpression of SEC23A partially enhanced the inflammation injury effects in LPS-induced HUVECs with overexpression of miR-29b-3p. Hence, miR-29b-3p repressed inflammatory response, cell apoptosis and promoted cell proliferation in LPS-induced HUVECs by targeting SEC23A, providing a potential target for treating sepsis.

A monoallelic SEC23A variant E599K associated with cranio-lenticulo-sutural dysplasia.

Cranio-lenticulo-sutural dysplasia (CLSD; MIM 607812) is a rare or underdiagnosed condition, as only two families have been reported. The original family (Boyadjiev et al., Human Genetics, 2003, 113, 1-9 and Boyadjiev et al., Nature Genetics, 2006, 38, 1192-1197) showed recessive inheritance of the condition with a biallelic SEC23A missense variant in affected individuals. In contrast, another child with sporadic CLSD had a monoallelic SEC23A variant inherited from the reportedly unaffected father (Boyadjiev et al., Clinical Genetics, 2011, 80, 169-176), raising questions on possible digenism. Here, we report a 2-month-old boy seen because of large fontanels with wide cranial sutures, a large forehead, hypertelorism, a thin nose, a high arched palate, and micrognathia. His mother was clinically unremarkable, while his father had a history of large fontanels in infancy who had closed only around age 10 years; he also had a large forehead, hypertelorism, a thin, beaked nose and was operated for bilateral glaucoma with exfoliation of the lens capsule. Trio genome sequencing and familial segregation revealed a monoallelic c.1795G > A transition in SEC23A that was de novo in the father and transmitted to the proband. The variant predicts a nonconservative substitution (p.E599K) in an ultra-conserved residue that is seen in 3D models of yeast SEC23 to be involved in direct binding between SEC23 and SAR1 subunits of the coat protein complex II coat. This observation confirms the link between SEC23A variants and CLSD but suggests that in addition to the recessive inheritance described in the original family, SEC23A variants may result in dominant inheritance of CLSD, possibly by a dominant-negative disruptive effect on the SEC23 multimer.

SEC23A Inhibit Melanoma Metastatic through Secretory PF4 Cooperation with SPARC to Inhibit MAPK Signaling Pathway.

Metastasis of melanoma to the distant organs is a multistep process in which the tumor microenvironment (TME) may play an important role. However, the relationship between metastatic progression and TME is intricate. In the present study, using melanoma derivative cell lines OL (oligometastatic) and POL (polymetastatic) that differ in their metastatic colonization capability, we have elucidated a new mechanism involving "SEC23A-PF4-MAPK/ERK axis" in which PF4 transported by COPII hinders metastasis through inhibition of MAPK/ERK signaling pathway. Furthermore, SPARC can act cooperatively to enhance the inhibition of Pf4 on ERK phosphorylation and melanoma cell metastasis. Our findings show the possibility of targeting cancer cell secretome for therapeutic development.

SEC23A Is an Independent Prognostic Biomarker in Bladder Cancer Correlated With MAPK Signaling.

Clinical data mining and bioinformatics analysis can be employed effectively to elucidate the function and underlying mechanisms of the gene of interest. Here, we have proposed a framework for the identification and validation of independent biomarkers in human cancer and for mechanistic profiling using gene sets enrichment analysis and pathway analysis. This is followed by validation with in vitro experiments. Using this framework to analyze the clinical relevance of SEC23A, we have discovered the prognostic potential of SEC23A in different cancers and identified SEC23A as an independent prognostic factor for poor prognosis in bladder cancer, which implicates SEC23A, for the first time, as an oncogene. Bioinformatic analyses have elucidated an association between SEC23A expression and the upregulation of the MAPK signaling pathway. Using the T24 human bladder cell line, we confirmed that knockdown of SEC23A expression could effectively impact the MAPK signaling pathway. Further, through PCR verification, we showed that MEF2A, one of the key genes of the MAPK signaling pathway, might be a downstream factor of the SEC23A gene.

Localised Collagen2a1 secretion supports lymphatic endothelial cell migration in the zebrafish embryo.

The lymphatic vasculature develops primarily from pre-existing veins. A pool of lymphatic endothelial cells (LECs) first sprouts from cardinal veins followed by migration and proliferation to colonise embryonic tissues. Although much is known about the molecular regulation of LEC fate and sprouting during early lymphangiogenesis, we know far less about the instructive and permissive signals that support LEC migration through the embryo. Using a forward genetic screen, we identified mbtps1 and sec23a, components of the COP-II protein secretory pathway, as essential for developmental lymphangiogenesis. In both mutants, LECs initially depart the cardinal vein but then fail in their ongoing migration. A key cargo that failed to be secreted in both mutants was a type II collagen (Col2a1). Col2a1 is normally secreted by notochord sheath cells, alongside which LECs migrate. col2a1a mutants displayed defects in the migratory behaviour of LECs and failed lymphangiogenesis. These studies thus identify Col2a1 as a key cargo secreted by notochord sheath cells and required for the migration of LECs. These findings combine with our current understanding to suggest that successive cell-to-cell and cell-matrix interactions regulate the migration of LECs through the embryonic environment during development.

Sec23a mediates miR-200c augmented oligometastatic to polymetastatic progression.

BACKGROUND: Cancer treatment is based on tumor staging. Curative intent is only applied to localized tumors. Recent studies show that oligometastatic patients who have limited number of metastases may benefit from metastasis-directed local treatments to achieve long-term survival. However, mechanisms underlying oligometastatic to polymetastatic progression remains elusive. METHODS: The effects of miR-200c and Sec23a on tumor metastasis were verified both in vitro and in vivo. The secretome changes were detected by mass spectrometry. FINDINGS: We established a pair of homologous lung-metastasis derived oligometastatic and polymetastatic cell lines from human melanoma cancer cell line M14. Using the two cell lines, we have identified Sec23a, a gene target of miR-200c, suppresses miR-200c augmented oligometastatic to polymetastatic progression via its secretome. Firstly, miR-200c over-expression and Sec23a interference accelerated oligometastatic to polymetatic progression. Secondly, Sec23a functions downstream of miR-200c. Thirdly, mass spectrometric analysis of the secretory protein profile suggests that Sec23a-dependent secretome may impact metastatic colonization by modifying tumor microenvironment. Fourthly, the survival analysis using The Cancer Genome Atlas database shows Sec23a as a favorable prognostic marker for skin cutaneous melanoma, supporting the clinical relevance of our findings. INTERPRETATION: The finding that Sec23a is a suppressor of oligometastatic to polymetastatic progression has clinical implications. First, it provides a new theoretical framework for the development of treatments that prevent oligometastasis to polymetastasis. Second, Sec23a may be used as a favorable prognostic marker for the selection of patients with stable oligometastatic disease for oligometastasis-based local therapies of curative intent. FUND: National Natural Science Foundations of China.

Identification of Cysteine Ubiquitylation Sites on the Sec23A Protein of the COPII Complex Required for Vesicle Formation from the ER.

BACKGROUND: COPII is a multiprotein complex that surrounds carrier vesicles budding from the Endoplasmic Reticulum and allows the recruitment of secretory proteins. The Sec23a protein plays a crucial role in the regulation of the dynamics of COPII formation ensuring the proper function of the secretory pathway. OBJECTIVE: Since few evidences suggest that ubiquitylation could have a role in the COPII regulation, the present study was aimed to establish whether the Sec23a component of the vesicular envelope COPII could be ubiquitylated. METHOD: Sec23a ubiquitylation was revealed by co-immunoprecipitation experiments. Recombinant Sec23a was gel-purified and analyzed by mass spectrometry subjected to trypsin proteolysis. Signature peptides were identified by the presence of Gly-Gly remnants from the C-terminus of the ubiquitin attached to the amino acid residues of the substrate. Recombinant Sec23a proteins bearing mutations in the ubiquitylation sites were used to evaluate the effect of ubiquitylation in the formation of COPII. RESULTS: We identified two cysteine ubiquitylation sites showed at position 432 and 449 of the Sec23a protein sequence. Interestingly, we revealed that the amino acid residues of Sec23a joined to ubiquitin were cysteine instead of the conventional lysine residues. This unconventional ubiquitylation consists of the addition of one single ubiquitin moiety that is not required for Sec23a degradation. Immunofluorescence results showed that Sec23a ubiquitylation might influence COPII formation by modulating Sec23a interaction with the ER membrane. Presumably, this regulation could occur throughout continual ubiquitylation/de-ubiquityliation cycles. CONCLUSION: Our results suggest a novel regulatory mechanism for the Sec23a function that could be crucial in several pathophysiological events known to alter COPII recycling.

miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1.

BACKGROUND: Treatment options for metastatic castrate-resistant prostate cancer (mCRPC) are limited and typically are centered on docetaxel-based chemotherapy. We previously reported that elevated miR-375 levels were significantly associated with poor overall survival of mCRPC patients. In this study, we evaluated if miR-375 induced chemo-resistance to docetaxel through regulating target genes associated with drug resistance. METHODS: We first compared miR-375 expression level between prostate cancer tissues and normal prostate tissues using data from The Cancer Genome Atlas (TCGA). To examine the role of miR-375 in docetaxel resistance, we transfected miR-375 using a pre-miRNA lentiviral vector and examined the effects of exogenously overexpressed miR-375 on cell growth in two prostate cancer cell lines, DU145 and PC-3. To determine the effect of overexpressed miR-375 on tumor growth and chemo-resistance in vivo, we injected prostate cancer cells overexpressing miR-375 into nude mice subcutaneously and evaluated tumor growth rate during docetaxel treatment. Lastly, we utilized qRT-PCR and Western blot assay to examine two miR-375 target genes, SEC23A and YAP1, for their expression changes after miR-375 transfection. RESULTS: By examining 495 tumor tissues and 52 normal tissues from TCGA data, we found that compared to normal prostate, miR-375 was significantly overexpressed in prostate cancer tissues (8.45-fold increase, p value = 1.98E-23). Docetaxel treatment induced higher expression of miR-375 with 5.83- and 3.02-fold increases in DU145 and PC-3 cells, respectively. Interestingly, miR-375 appeared to play a dual role in prostate cancer proliferation. While miR-375 overexpression caused cell growth inhibition and cell apoptosis, elevated miR-375 also significantly reduced cell sensitivity to docetaxel treatment in vitro, as evidenced by decreased apoptotic cells. In vivo xenograft mouse study showed that tumors with increased miR-375 expression were more tolerant to docetaxel treatment, demonstrated by greater tumor weight and less apoptotic cells in miR-375 transfected group when compared to empty vector control group. In addition, we examined expression levels of the two miR-375 target genes (SEC23A and YAP1) and observed significant reduction in the expression at both protein and mRNA levels in miR-375 transfected prostate cancer cell lines. TCGA dataset analysis further confirmed the negative correlations between miR-375 and the two target genes (r = -0.62 and -0.56 for SEC23A and YAP1, respectively; p < 0.0001). CONCLUSIONS: miR-375 is involved in development of chemo-resistance to docetaxel through regulating SEC23A and YAP1 expression. Our results suggest that miR-375 or its target genes, SEC23A or YAP1, might serve as potential predictive biomarkers to docetaxel-based chemotherapy and/or therapeutic targets to overcome chemo-resistance in mCRPC stage.

MicroRNA-21 promotes proliferation, migration, and invasion of colorectal cancer, and tumor growth associated with down-regulation of sec23a expression.

BACKGROUND: MicroRNA-21 (miR-21) is up-regulated in many cancers, including colorectal cancer (CRC). Nevertheless, the function of miR-21 in CRC and the mechanism underlying that function is still unclear. METHODS: After analyzing the expression of miR-21 and Sec23A in CRC cell lines, we transfected the highest miR-21 expressing cell line, SW-480, with a plasmid containing an miR-21 inhibitor and the lowest miR-21 expressing cell line, DLD-1, with a plasmid containing an miR-21 mimic and measured the effects on the expression of Sec23A and on cell proliferation, migration, and invasion. We also evaluated the effect of knocking down Sec23A on miR-21 expression and its effects on cell proliferation, migration, and invasion. Finally, we assessed the effect of miR-21 in a xenograft tumor model in mice. Tumor tissues from these mice were subjected to immunohistochemical staining to detect the expression of Sec23A. RESULTS: Genetic deletion of miR-21 suppressed the proliferation, migration, and invasion of SW-480 cells, while over-expression of miR-21 promoted proliferation, migration, and invasion of DLD-1 cells. Inhibition of miR-21 increased the expression of Sec23A protein in SW-480 cells while over-expression of miR-21 significantly suppressed the expression of Sec23A protein and Sec23A mRNA in DLD-1 cells. Knockdown of Sec23A increased the expression of miR-21 in SW480 and DLD-1 cells and their proliferation (DLD-1 only), migration, and invasion. Over-expression of miR-21 promoted tumor growth in BALB/c nude mice and suppressed tumor expression of Sec23A. CONCLUSION: These findings provide novel insight into the molecular functions of miR-21 in CRC, which may serve as a potential interesting target.