SP4 Facilitates Esophageal Squamous Cell Carcinoma Progression by Activating PHF14 Transcription and Wnt/Β-Catenin Signaling.

Specificity protein 4 transcription factor (SP4), a member of the Sp/Krüppel-like family (KLF), could bind to GT and GC box promoters, and plays an essential role in transcriptional activating. Despite SP4 having been detected to be highly expressed in a variety of human tumors, its biological effect and underlying molecular mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. Our research discovered that high SP4 expression is detected in primary ESCC specimens and cell lines and is strongly associated with the ESCC tumor grade and poor prognosis. In vitro, knockdown of SP4 suppressed cell proliferation and cell-cycle progression and promoted apoptosis, whereas overexpression of SP4 did the opposite. In vivo, inhibiting SP4 expression in ESCC cells suppresses tumor growth. Subsequently, we demonstrated that SP4 acts as the transcriptional upstream of PHF14, which binds to PHF14 promoter region, thus promoting PHF14 transcription. PHF14 was also significantly expressed in patient tissues and various ESCC cell lines and its expression promoted cell proliferation and inhibited apoptosis. Moreover, knockdown of SP4 inhibited the Wnt/ß-catenin signaling pathway, whereas overexpression of PHF14 eliminated the effects of SP4 knockdown in ESCC cells. These results demonstrate that SP4 activates the Wnt/ß-catenin signaling pathway by driving PHF14 transcription, thereby promoting ESCC progression, which indicates that SP4 might act as a prospective prognostic indicator or therapeutic target for patients with ESCC. IMPLICATIONS: This study identified SP4/PH14 axis as a new mechanism to promote the progression of ESCC, which may serve as a novel therapeutic target for patients with ESCC.

Corrigendum: Dihydrocapsaicin inhibits cell proliferation and metastasis in melanoma via down-regulating ß-catenin pathway.

[This corrects the article DOI: 10.3389/fonc.2021.648052.].

Erratum: Lycorine hydrochloride inhibits melanoma cell proliferation, migration and invasion via down-regulating p21Cip1/WAF1.

[This corrects the article on p. 1391 in vol. 11, PMID: 33948364.].

RFTN1 facilitates gastric cancer progression by modulating AKT/p38 signaling pathways.

Gastric cancer (GC), a malignant tumor originating from the epithelium of the gastric mucosa, has been endangering human health for many years. The current standard surgical resection is not ideal for advanced gastric cancer. Therefore, it is urgent to find new prognostic indicators as well as drug targets. In our study, referring to clinicopathological characteristics of GC, we found that raftlin lipid raft linker 1 (RFTN1) had high expression in primary GC tissues. Subsequently, we showed that knockdown of RFTN1 inhibited GC cell proliferation and induced cell cycle arrest in G0/G1 phase, and promoted GC cell apoptosis. Conversely, overexpression of RFTN1 promoted GC cell proliferation and G0/G1 to S phase transition, and inhibited apoptosis. Furthermore, cell derived xenograft experiments showed that knockdown of RFTN1 inhibited GC cell growth in vivo. Notably, our experimental data demonstrated that knockdown of RFTN1 could inhibit the AKT signaling pathway and activate p38 signaling pathway, whereas overexpression of RFTN1 did the opposite. Moreover, the effects caused by knockdown of RFTN1 in GC cells could be rescued by using SC79 (an AKT activator). In conclusion, these results indicated that RFTN1 plays an oncogenic role in GC, and might act as a prospective prognostic indicator or therapeutic target for GC patients.

Identification of Early Diagnostic and Prognostic Biomarkers via WGCNA in Stomach Adenocarcinoma.

Stomach adenocarcinoma (STAD) is a leading cause of cancer deaths, and the outcome of the patients remains dismal for the lack of effective biomarkers of early detection. Recent studies have elucidated the landscape of genomic alterations of gastric cancer and reveal some biomarkers of advanced-stage gastric cancer, however, information about early-stage biomarkers is limited. Here, we adopt Weighted Gene Co-expression Network Analysis (WGCNA) to screen potential biomarkers for early-stage STAD using RNA-Seq and clinical data from TCGA database. We find six gene clusters (or modules) are significantly correlated with the stage-I STADs. Among these, five hub genes, i.e., MS4A1, THBS2, VCAN, PDGFRB, and KCNA3 are identified and significantly de-regulated in the stage-I STADs compared with the normal stomach gland tissues, which suggests they can serve as potential early diagnostic biomarkers. Moreover, we show that high expression of VCAN and PDGFRB is associated with poor prognosis of STAD. VCAN encodes a large chondroitin sulfate proteoglycan that is the main component of the extracellular matrix, and PDGFRB encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor (PDGF) family. Consistently, Gene Ontology (GO) analysis of differentially expressed genes in the STADs indicates terms associated with extracellular matrix and receptor ligand activity are significantly enriched. Protein-protein network interaction analysis (PPI) and Gene Set Enrichment Analysis (GSEA) further support the core role of VCAN and PDGFRB in the tumorigenesis. Collectively, our study identifies the potential biomarkers for early detection and prognosis of STAD.

Lycorine hydrochloride inhibits melanoma cell proliferation, migration and invasion via down-regulating p21Cip1/WAF1.

Lycorine hydrochloride (LH) is an active ingredient sourced from the medicinal herb Lycoris radiata. Previous studies have suggested that LH exerts tumor suppression activity in several human cancers. However, the anti-cancer effect of LH in melanoma and the potential molecular mechanisms still need to be further studied. p21Cip1/WAF1, unlike its traditional cyclin-dependent kinase (CDK) inhibitor role, is believed to act as an oncogene under certain cellular conditions. In this research, an increased expression of p21Cip1/WAF1 was found in human melanoma tissues and positively related to the tumor invasion depth. High level of p21Cip1/WAF1 was found to correlate with bad outcomes of melanoma patients by Kaplan-Meier survival analysis. Functional experiments demonstrated that the proliferation, migration and invasion ability of A375 and MV3 melanoma cells was powerfully inhibited by LH through inducing S phase cell cycle arrest and regulating epithelial-mesenchymal transition (EMT). In NOD/SCID mice model, LH effectively inhibited the xenograft tumor growth and lung metastasis of A375 cells. Further research revealed that LH reduced p21Cip1/WAF1 protein by accelerating its ubiquitination. Importantly, the LH-induced suppression of cell proliferation and metastasis was rescued by p21Cip1/WAF1 overexpression, both in vitro an in vivo. Taken together, LH, which suppresses the proliferation and metastasis of melanoma cells via down-regulating p21Cip1/WAF1, is expected to be developed as an effective medicine for melanoma therapy.

Dihydrocapsaicin Inhibits Cell Proliferation and Metastasis in Melanoma via Down-regulating ß-Catenin Pathway.

Dihydrocapsaicin (DHC) is one of the main components of capsaicinoids in Capsicum. It has been reported that DHC exerts anti-cancer effects on diverse malignant tumors, such as colorectal cancer, breast cancer, and glioma. However, studies focused on the effect of DHC upon melanoma have rarely been done. In the present study, melanoma A375 and MV3 cell lines were treated with DHC and the cell proliferation, migration, and invasion were significantly suppressed. Furthermore, DHC effectively inhibited xenograft tumor growth and pulmonary metastasis of melanoma cells in NOD/SCID mice model. It was identified that ß-catenin, which plays significant roles in cell proliferation and epithelial-mesenchymal transition, was down-regulated after DHC treatment. In addition, cyclin D1, c-Myc, MMP2, and MMP7, which are critical in diverse cellular process regulation as downstream proteins of ß-catenin, were all decreased. Mechanistically, DHC accelerates ubiquitination of ß-catenin and up-regulates the beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) in melanoma cells. The DHC induced suppression of cell proliferation, migration, and invasion were partly rescued by exogenous ß-catenin overexpression, both in vitro and in vivo. Taken together, DHC may serve as a candidate natural compound for human melanoma treatment through ß-catenin pathway.

Bmintegrin ß1: A broadly expressed molecule modulates the innate immune response of Bombyx mori.

Integrins are transmembrane glycoproteins that are broadly distributed in living organisms. As a heterodimer, they contain an α and a ß subunit, which are reported to be associated with various physiological and pathological processes. In the present study, a 2502 bp full-length cDNA sequence of Bmintegrin ß1 was obtained from the silkworm, Bombyx mori. Bmintegrin ß1 belongs to the ß subunit of the integrin family and contains several typical structures of integrins. Gene expression profile analysis demonstrated that Bmintegrin ß1 was ubiquitously expressed in all tested tissues and organs, with the maximum expression levels in fat body and hemocytes. The immunofluorescence results showed that Bmintegrin ß1 was located in the cell membrane and widely distributed in fat bodies and different types of hemocytes. Bmintegrin ß1 expression was remarkably increased after challenging with different kinds of bacteria and pathogen-associated molecular patterns (PAMPs). Further investigation revealed that Bmintegrin ß1 could participate in the agglutination of pathogenic bacteria possibly through direct binding with the relative bacteria and PAMPs. Altogether, this study provides a novel insight into the immune functional features of Bmintegrin ß1.

Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer.

BACKGROUND: Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment. METHODS: The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry). RESULTS: In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14-1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer. CONCLUSIONS: The efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.

MYST1/KAT8 contributes to tumor progression by activating EGFR signaling in glioblastoma cells.

With short survival time, glioblastoma (GBM) is the most malignant tumor in the central nervous system. Recently, epigenetic enzymes play essential roles in the regulation of tumorigenesis and cancer development of GBM. However, little is known about MYST1/KAT8/MOF, a histone acetylation enzyme, in GBM. The present study shows that MYST1 promotes GBM progression through activating epidermal growth factor receptor (EGFR) signaling. MYST1 expression was increased in GBM and was negatively correlated with prognosis in patients with glioma and GBM. Knockdown of MYST1 reduced cell proliferation and BrdU incorporation in LN229, U87, and A172 GBM cells. Besides, MYST1 downregulation also induced cell cycle arrest at G2M phase, as well as the reduced expression of CDK1, Cyclin A, Cyclin B1, and increased expression of p21CIP1/Waf1 . Meanwhile, Self-renewal capability in vitro and tumorigenecity in vivo were also impaired after MYST1 knockdown. Importantly, MYST1 expression was lowly expressed in mesenchymal subtype of GBM and was positively correlated with EGFR expression in a cohort from The Cancer Genome Atlas. Western blot subsequently confirmed that phosphorylation and activation of p-Try1068 of EGFR, p-Ser473 of AKT and p-Thr202/Tyr204 of Erk1/2 were also decreased by MYST1 knockdown. Consistent with the results above, overexpression of MYST1 promoted GBM growth and activated EGFR signaling in vitro and in vivo. In addition, erlotinib, a US Food and Drug Administration approved cancer drug which targets EGFR, was able to rescue MYST1-promoted cell proliferation and EGFR signaling pathway. Furthermore, the transcription of EGF, an EFGR ligand, was shown to be positively regulated by MYST1 possibly via H4K16 acetylation. Our findings elucidate MYST1 as a tumor promoter in GBM and an EGFR activator, and may be a potential drug target for GBM treatment.