Sorcin Inhibits Mitochondrial Apoptosis by Interacting with STAT3 via NF-κB Pathway.

Hepatocellular carcinoma (HCC) is a common tumor. Our group has previously reported that sorcin (SRI) plays an important role in the progression and prognosis of HCC. This study aims to explore the mechanism of SRI inhibiting the mitochondrial apoptosis. Bioinformatics analysis, co-IP and immunofluorescence were used to analyze the relationship between SRI and STAT3. MMP and Hoechst staining were performed to detect the effect of SRI on cell apoptosis. The expression of apoptosis-related proteins and NF-κB signaling pathway were examined by Western blot and immunohistochemistry when SRI overexpression or underexpression in vivo and in vitro were found. Moreover, inhibitors were used to further explore the molecular mechanism. Overexpression of SRI inhibited cell apoptosis, which was attenuated by SRI knockdown in vitro and in vivo. Moreover, we identified that STAT3 is an SRI-interacting protein. Mechanistically, SRI interacts with STAT3 and then activates the NF-κB signaling pathway in vitro and in vivo. SRI interacting with STAT3 inhibits apoptosis by the NF-κB pathway and further contributes to the proliferation in HCC, which offers a novel clue and a new potential therapeutic target for HCC.

Sorcin promotes proliferation of hepatocellular carcinoma by regulating VEGFA/B via PI3K pathway.

Hepatocellular carcinoma (HCC) is a highly vascularized tumor, one of the most common and lethal cancer-related tumor deaths worldwide, with cell proliferation playing a key role. In this study our western blot results and data from TAGC demonstrate a strong association between Sorcin (SRI) overexpression and poor outcomes in HCC. Moreover, SRI overexpression was remarkably effective in promoting proliferation in vitro and increasing tumor growth in vivo, which were attenuated by knocking down SRI. Mechanistically, SRI regulated vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor B (VEGFB) through PI3K/Akt/FOXO1 signal pathway. Overall, our study indicates that SRI stimulates HCC growth by controlling VEGFA/B, which presents a fresh insight into the pathogenesis of hepatocarcinogenesis and a new therapeutic target for HCC.

Retraction Notice to: A Novel Mechanism of Doxorubicin Resistance and Tumorigenesis Mediated by MicroRNA-501-5p-Suppressed BLID.

[This retracts the article DOI: 10.1016/j.omtn.2018.06.011.].

Pentraxin-3 inhibits milky spots metastasis of gastric cancer by inhibiting M2 macrophage polarization.

Purpose: Recent studies have indicated that Pentraxin-3 (PTX3) is related to invasion, migration and metastasis of gastric cancer cells (GCCs). However, the function of PTX3 in stemness and tumor-associated macrophages (TAMs) polarization in GC has not yet been revealed. Here, we investigated the role of PTX3 in TAMs polarization and stemness in gastric cancer (GC), and further explored the effect of PTX3 on milky spot metastasis of gastric cancer. Methods: PTX3 expression in human gastric cancer tissues was examined with immunohistochemistry (IHC). The influence on stemness of gastric cancer cells was examined by sphere formation assay and western blot. qRT-PCR, IHC and flow cytometry were used to evaluate M1/M2 macrophage signatures. The effects of PTX3 on TAM polarization and milky spots were investigated in vitro and in vivo. The possible mechanism of PTX3 on targeted cytokines and pathway were analyzed by qRT-PCR and western blot. Results: We found that PTX3 was low expressed in gastric carcinoma tissues and associated with stemness and polarization of macrophages. The upregulation of PTX3 inhibited the stemness of GCCs. Furthermore, PTX3 suppressed the polarization of M2 macrophages in the milky spots in vivo and in vitro and inhibited the metastasis of GC into milky spots. PTX3 restrained the expression of interleukin-4 (IL-4) and IL-10 via the inhibition of phosphorylation of the c-Jun N-terminal protein kinase 1/2 (JNK1/2) in GCCs. Conclusion: These results revealed a novel mechanism of PTX3 in GC, which may participate in the development and metastasis of GC by affecting stemness and macrophage polarization. PTX3 should be considered as a crucial biomarker and may be potentially used in targeted therapy in GC progression.

The Role of KDM2B and EZH2 in Regulating the Stemness in Colorectal Cancer Through the PI3K/AKT Pathway.

Background: The incidence of colorectal cancer (CRC) has been increasing worldwide in recent years. Targeting cancer stem cells (CSCs) in CRC remains a difficult challenge. KDM2B and EZH2 play important role in the maintenance of CSCs' self-renewal capacity and tumorigenic ability; however, the biological functions of those genes in CRC remain unclear. In this study, we aimed to define the contribution of the expression of KDM2B in the features of CRC and establish the relationship between KDM2B and EZH2 in colorectal CSCs. Methods: The expression of KDM2B and EZH2 in the specimens of CRC and CRC cell lines were analyzed by immunohistochemistry, Western blot, and immunofluorescence. The underlying mechanisms of altered expressions of KDM2B and EZH2 and their impact on the biologic features of CRC and stemness in CRC were investigated. Results: The KDM2B gene was highly expressed in CRC tissues, and its overexpression positively correlated with tumor stages and tumor/node/metastasis (TNM) classification. The downregulation of KDM2B retarded cell proliferation, induced DNA damage, reduced spheroid formation, and decreased CRC stem cell markers: CD44, CD133, and ALDH-1. Moreover, the downregulation of KDM2B decreased the expression of EZH2 and both regulated cell migration, invasion, and stemness in the CRC cell line. Additionally, the interaction between KDM2B and EZH2 significantly increased the components of the PI3K/AKT pathway including AKT and PI3K. The high expression of KDM2B positively correlated with EZH2 in CRC tissues. Conclusion: This study shows that the downregulation of KDM2B and EZH2 can regulate CRC cell stemness, and their interaction may serve as a novel prognostic marker and therapeutic target for patients with CRC.

AnnexinA7 promotes epithelial-mesenchymal transition by interacting with Sorcin and contributes to aggressiveness in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and metastasis is the major cause of the high mortality of HCC. In this study, we identified that AnnexinA7 (ANXA7) and Sorcin (SRI) are overexpressed and interacting proteins in HCC tissues and cells. In vitro functional investigations revealed that the interaction between ANXA7 and SRI regulated epithelial-mesenchymal transition (EMT), and then affected migration, invasion, and proliferation in HCC cells. Furthermore overexpression/knockdown of ANXA7 was remarkably effective in promoting/inhibiting tumorigenicity and EMT in vivo. Altogether, our study unveiled a mechanism that ANXA7 promotes EMT by interacting with SRI and further contributes to the aggressiveness in HCC, which provides a novel potential therapeutic target for preventing recurrence and metastasis in HCC.

The potential mechanism of action of Sorcin and its interacting proteins.

Sorcin (Soluble resistance-related calcium binding protein) is a calcium binding oncoprotein. Sorcin is overexpressed in several human tumors and cancer cells lines which confers multidrug resistance (MDR) to these cells. This review summarizes the biochemical functions of Sorcin which includes modulation of calcium homeostasis, apoptosis, and cancer metastasis. Sorcin is involved in various biological processes by interacting with other proteins, such as p-glycoprotein, programmed cell death protein 6, tumor necrosis factor receptor-associated protein 1, Annexin A7, polo-like kinase 1, HCV nonstructural 5A, signal transducer and activator of transcription 3, presenilin 2, α-synuclein, Ca2+-release channel and others. A deeper look into the function and interacting partners of Sorcin sheds more light on the possible effects of its physical activity and more elaborately, exploring the role of Sorcin in future research prospects.

Cisatracurium Retards Cell Migration and Invasion Upon Upregulation of p53 and Inhibits the Aggressiveness of Colorectal Cancer.

Colorectal cancer (CRC) is reported to be the third and fourth, most diagnosed and cause of cancer associated deaths respectively. In 2012 for instance, about 1.4 million new cases were reported, and approximately 700,000 deaths recorded. Survival from CRC is dependent on the stage at which it is diagnosed coupled with appropriate surgical and medical intervention. Cisatracurium is widely used for skeletal muscle relaxation during abdominal surgeries, including bowel and colon surgeries. Recent studies reported that cisatracurium inhibits progression of human cancer cells, however, the mechanisms leading to the inhibition are yet to be completely understood. To elucidate mechanisms resulting particularly in tumor cell growth and metastasis, we developed ex vivo and in in vivo xenograft models of CRC. Cisatracurium caused upregulation of p53 and its down-stream genes and proteins known to regulate proliferation and metastasis in vitro and in vivo. Genomic analyses of CRC following cisatracurium treatment revealed moderate to high DNA damage, while functional analyses demonstrated significant tumor cells growth regression, as well as repression of migration and invasion. Importantly, cisatracurium increased E-Cadherin and CALD-1 but decreased SNAI-1 and SLUG levels in vitro and in vivo. Together, the findings demonstrate that elevation of p53 upon cisatracurium-induced genomic injury, represent a potential mechanism by which cisatracurium result in the suppression of CRC progression and metastasis.

miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD.

BACKGROUND: Cervical cancer is the common gynecological deadly malignancy worldwide. Here we attempted to evaluate the effects and mechanisms of microRNA-501-5p (miR-501) on the cell proliferation, migration, invasion and the clinical significance in the cervical cancer. METHODS: Cervical cancer HeLa cells were transfected with miR-501 mimic or inhibitor or siRNA against Cylindromatosis (CYLD) using Lipofectamine 2000. miR-501 expression was assessed in HeLa cells and cervical cancer specimens by real-time qRT-PCR. The functional roles of miR-501 were determined by CCK-8, colony formation, scratch wound healing and transwell assays. The apoptosis rate was detected by flow cytometry assay. CYLD, BCL-2, BAX, NF-κB p65 and phosphorylated p65 (p-p65) proteins were examined by Western blotting. CYLD expression was evaluated by immunohistochemistry in cervical cancer tissues. RESULTS: miR-501 was upregulated, whereas CYLD protein was downregulated in cervical cancer tissues compared to normal cervical tissues. miR-501 overexpression and CYLD protein downregulation were positively correlated with poor differentiation, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. CYLD was downregulated by miR-501 at both mRNA and protein levels in HeLa cells. miR-501 promoted cell proliferation, migration and invasion in cervical cancer, while inhibited the apoptosis. This is possibly due to the downregulation of CYLD and subsequent activation of NF-κB p65. CONCLUSIONS: miR-501 upregulation and CYLD downregulation are associated with the development and progression of cervical cancer. miR-501 promotes cervical cancer cell proliferation, migration and invasion possibly via downregulating CYLD and subsequently activating NF-κB p65. miR-501 might be a potential therapeutic target for cervical cancer.

A Novel Mechanism of Doxorubicin Resistance and Tumorigenesis Mediated by MicroRNA-501-5p-Suppressed BLID.

Doxorubicin is a widely used anthracycline-based anti-tumor agent for both solid and liquid tumors. Mounting evidence has demonstrated that microRNAs (miRNAs) are involved in chemoresistance and tumorigenesis. However, the roles of microRNA-501-5p (miR-501) in doxorubicin resistance and gastric cancer cell proliferation and invasion are still not fully understood. In this study, we identified that BLID (BH3-like motif-containing protein, cell death inducer) was directly regulated by miR-501 at the post-transcriptional level in multiple gastric cancer cell lines. Endogenous miR-501 was higher, whereas BLID was lower, in doxorubicin-resistant gastric cancer SGC7901/ADR cells compared with their parental SGC7901 cells. miR-501 suppressed gastric cancer cell apoptosis, induced resistance to doxorubicin, and enhanced cell proliferation, migration, and invasion. Subcutaneous injection of miR-501 lentivirus-infected SGC7901 cells resulted in rapid growth of xenograft tumors and resistance to doxorubicin treatment, unlike injection of negative miRNA lentivirus-infected SGC7901 cells. This is achieved at least partially by directly targeting BLID and subsequent inactivation of caspase-9 and caspase-3 and phosphorylation of Akt. Taken together, miR-501 induces doxorubicin resistance and enhances the tumorigenesis of gastric cancer cells by suppressing BLID. miR-501 might be a potential target for doxorubicin resistance and gastric cancer therapy.