Jing Yuan's research while affiliated with First Affiliated Hospital of China Medical University and other places

Background Cancer stem cells (CSCs) are a small population of cells in tumor tissues that can drive tumor initiation and promote tumor progression. A small number of previous studies indirectly mentioned the role of F-box and WD repeat domain-containing 7 (FBXW7) as a tumor suppressor in Triple-negative breast cancer (TNBC). However, few studies have focused on the function of FBXW7 in cancer stemness in TNBC and the related mechanism. Methods We detected FBXW7 by immunohistochemistry (IHC) in 80 TNBC patients. FBXW7 knockdown and overexpression in MD-MBA-231 and HCC1937 cell models were constructed. The effect of FBXW7 on malignant phenotype and stemness was assessed by colony assays, flow cytometry, transwell assays, western blot, and sphere formation assays. Immunoprecipitation-Mass Spectrometry (IP-MS) and ubiquitination experiments were used to find and verify potential downstream substrate proteins of FBXW7. Animal experiments were constructed to examine the effect of FBXW7 on tumorigenic potential and cancer stemness of TNBC cells in vivo. Results The results showed that FBXW7 was expressed at low levels in TNBC tissues and positively correlated with prognosis of TNBC patients. In vitro, FBXW7 significantly inhibited colony formation, cell cycle progression, cell migration, EMT process, cancer stemness and promotes apoptosis. Further experiments confirmed that chromodomain-helicase-DNA-binding protein 4 (CHD4) is a novel downstream target of FBXW7 and is downregulated by FBXW7 via proteasomal degradation. Moreover, CHD4 could promote the nuclear translocation of β-catenin and reverse the inhibitory effect of FBXW7 on β-catenin, and ultimately activate the Wnt/β-catenin pathway. Rescue experiments confirmed that the FBXW7-CHD4-Wnt/β-catenin axis was involved in regulating the maintenance of CSC in TNBC cells. In animal experiments, FBXW7 reduced CSC marker expression and suppressed TNBC cell tumorigenesis in vivo. Conclusions Taken together, these results highlight that FBXW7 degrades CHD4 protein through ubiquitination, thereby blocking the activation of the Wnt/β-catenin pathway to inhibit the stemness of TNBC cells. Thus, targeting FBXW7 may be a promising strategy for therapeutic intervention against TNBC.

Distant metastasis is a major cause of increased mortality in breast cancer patients, but the mechanisms underlying breast cancer metastasis remain poorly understood. In this study, we aimed to identify a metastasis-related gene (MRG) signature for predicting progression in breast cancer. By screening using three regression analysis methods, a 9-gene signature (NOTCH1, PTP4A3, MMP13, MACC1, EZR, NEDD9, PIK3CA, F2RL1 and CCR7) was constructed based on an MRG set in the BRCA cohort from TCGA. This signature exhibited strong robustness, and its generalizability was verified in the Metabric and GEO cohorts. Of the nine MRGs, EZR is an oncogenic gene with a well-documented role in cell adhesion and cell migration, but it has rarely been investigated in breast cancer. Based on a search of different databases, EZR was found to be significantly more highly expressed in both breast cancer cells and breast cancer tissue. EZR knockdown significantly inhibited cell proliferation, invasion, chemoresistance and EMT in breast cancer. Mechanistically, RhoA activation assays confirmed that EZR knockdown inhibited the activity of RhoA, Rac1 and Cdc42. In summary, we identified a nine-MRG signature that can be used as an efficient prognostic indicator for breast cancer patients, and owing to its involvement in regulating breast cancer metastasis, EZR might serve as a therapeutic target.

Aims This study aimed to observe the efficacy and safety of anlotinib in the treatment of small cell lung cancer (SCLC) in the real world, as first-line maintenance therapy, second-line, and above. Methods Clinical data of 109 patients with SCLC treated with anlotinib and hospitalized at The First Affiliated Hospital of Zhengzhou University from June 2018 to June 2020 were retrospectively analyzed. Analysis of short-term efficacy and survival was performed, with p<0.05 being considered statistically significant. Results The median progression-free survival (mPFS) of anlotinib monotherapy used as first-line maintenance treatment of SCLC was 6.3 months (11.7 months in the limited phase and 5.8 months in the extensive phase) and median overall survival (mOS) was 16.7 months (not reached in limited phase, 12.6 months in extensive phase). In second-line treatment, anlotinib with chemotherapy prolonged PFS and OS as compared to anlotinib monotherapy (p<0.05). In third-line and above treatment, there was no improvement in mPFS with the chemotherapy combination regimen compared to anlotinib monotherapy (3.6 months vs. 3.8 months, p=0.398), with a trend toward impaired mOS (8.5 months vs. not achieved, p=0.060). Univariate analyses and multivariate analyses revealed that Eastern Cooperative Oncology Group performance status and liver metastases were independent prognostic factors affecting PFS and OS. No new anlotinib-related adverse reactions were identified. Conclusion Anlotinib was effective for first-line maintenance and second-line treatment, and the chemotherapy combination regimen was superior to monotherapy when applied as second-line treatment. However, this trend was not observed in third-line and above therapy.

Platinum-based cytotoxic chemotherapy is considered the standard treatment for advanced gastric cancer (GC). However, cisplatin chemoresistance often occurs with the mechanisms being not well clarified, which results in the cancer recurrence and poor survival. Ginsenoside Rg3, isolated from the Chinese Herb Panax Ginseng, is recognized as an anti-cancer agent. Herein, we aimed to reveal whether Ginsenoside Rg3 alleviates cisplatin resistance and sensitizes GC cells to cisplatin-induced apoptosis, and draw out the underlying molecular mechanism in cisplatin-resistant GC cells. The lower expression of miR-429 was found in AGSR-CDDP cells; it was also in association with cisplatin-resistance in GC cells and expression of which was restored following Ginsenoside Rg3 treatment. We also demonstrated that miR-429 made a contribution toward chemosensitivity in GC cells partly through SOX2 regulation. SOX2 was found to contribute to developing platinum resistance and was an authentic target for miR-429 in AGSR-CDDP cells. Importantly, enforced expression of SOX2 with a pcDNA3-SOX2 construct lacking the 3′-UTR miRNA binding site diminished the cytotoxic effects of miR-429 in AGSR-CDDP cells. We demonstrated that Ginsenoside Rg3 enhanced chemosensitivity in AGSR-CDDP GC cells, at least in part, through up-regulating miR-429, thereby targeting SOX2 and modulating downstream PI3K/AKT/mTOR signaling. Ginsenoside Rg3 was also found to regulate apoptosis-related genes via miR-429 in cisplatin-resistant GC cells. Ginsenoside Rg3 treatment significantly suppressed the migration rate of AGSR-CDDP GC cells, while following transfection with anti-miR-429, the anti-migratory effects of Ginsenoside Rg3 was partially abolished. This data suggested that Ginsenoside Rg3 may impede the chemoresistance and migration of GC cells mainly mediated through miR-429. We concluded that miR-429-regulated SOX2 expression was one of the main mechanisms by which Ginsenoside Rg3 dramatically promoted its anticancer effects on cisplatin-resistant GC cells. We also underscored a supporting model in which miR-429 adjusted PI3K/AKT/mTOR signaling by regulating SOX2 in cisplatin-resistant GC cells.

Megakaryocytic leukemia 1 (MKL1) is a key transcription factor involved in non-small cell lung cancer (NSCLC) growth and metastasis. Yet, its downstream target genes, especially long non-coding RNA (lncRNA) targets, are poorly investigated. In this study, we employed lncRNA array technology to identify differentially expressed lncRNAs in NSCLC cells with or without overexpression of MKL1. Candidate lncRNAs were further explored for their clinical significance and function in NSCLC. The results showed that MKL1 promoted the expression of lncRNA SNHG18 in NSCLC cells. SNHG18 upregulation in NSCLC specimens correlated with lymph node metastasis and reduced overall survival of NSCLC patients. SNHG18 expression served as an independent prognostic factor for NSCLC. Knockdown of SNHG18 blocked MKL1-induced growth and invasion of NSCLC cells in vitro. Animal studies validated the requirement for SNHG18 in NSCLC growth and metastasis. Moreover, overexpression of SNHG18 promoted NSCLC cell proliferation and invasion. Mechanically, SNHG18 exerted its prometastatic effects on NSCLC cells through repression of miR-211-5p and induction of BRD4. Clinical evidence indicated that SNHG18 expression was negatively correlated with miR-211-5p expression in NSCLC tissues. Altogether, SNHG18 acts as a lncRNA mediator of MKL1 in NSCLC. SNHG18 facilitates NSCLC growth and metastasis by modulating the miR-211-5p/BRD4 axis. Therefore, SNHG18 may be a potential therapeutic target for the treatment of NSCLC.

Long non-coding RNA (lncRNA) LINC00173 has been previously shown to promote chemoresistance and progression of small-cell lung cancer. Herein, we examine the clinical significance and biological function of LINC00173 in triple-negative breast cancer (TNBC). Quantitative PCR analysis was performed to determine the expression of LINC00173 in TNBC and adjacent breast tissues (n = 84). The associations of LINC00173 expression with cancer features and survival of TNBC patients were analyzed. The function of LINC00173 in TNBC cell proliferation, colony formation, and invasion was explored. TNBCs expressed increased levels of LINC00173 relative to normal breast tissues. TNBC patients with high tumoral LINC00173 levels had a lower recurrence-free survival and overall survival rate than those with low LINC00173 expression. Silencing of LINC00173 inhibited the proliferation, colony formation, and invasion of TNBC cells, whereas overexpression of LINC00173 exerted opposite effects. In vivo studies confirmed the reduction of tumor growth by LINC00173 depletion. Mechanistic investigation revealed that LINC00173 suppressed miR-490-3p to promote aggressive phenotype in TNBC cells. There was an inverse correlation between miR-490-3p and LINC00173 in TNBC (r = -0.2647, P = 0.0149). Altogether, LINC00173 functions as an oncogene in TNBC through antagonization of miR-490-3p. Upregulation of LINC00173 is associated with poor prognosis in TNBC. Targeting LINC00173 provides a potential therapeutic strategy for TNBC.