Immunotherapy and the ovarian cancer microenvironment: Exploring potential strategies for enhanced treatment efficacy.

Despite progress in cancer immunotherapy, ovarian cancer (OC) prognosis continues to be disappointing. Recent studies have shed light on how not just tumour cells, but also the complex tumour microenvironment, contribute to this unfavourable outcome of OC immunotherapy. The complexities of the immune microenvironment categorize OC as a 'cold tumour'. Nonetheless, understanding the precise mechanisms through which the microenvironment influences the effectiveness of OC immunotherapy remains an ongoing scientific endeavour. This review primarily aims to dissect the inherent characteristics and behaviours of diverse cells within the immune microenvironment, along with an exploration into its reprogramming and metabolic changes. It is expected that these insights will elucidate the operational dynamics of the immune microenvironment in OC and lay a theoretical groundwork for improving the efficacy of immunotherapy in OC management.

TRPM7 is required for ovarian cancer cell growth, migration and invasion.

Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions.

Roles of TRPM7 in ovarian cancer.

Ovarian cancer stands as the prevailing gynecologic malignancy, afflicting over 313,959 individuals annually worldwide, accompanied by more than 207,252 fatalities. Perturbations in calcium signaling contribute significantly to the pathogenesis of numerous cancers, including ovarian cancer, wherein alterations in calcium transporter expression have been reported. Overexpression of TRPM7, a prominent calcium transporter, has been linked to adverse prognostic outcomes in various cancer types. The focus of this comprehensive review centers around delineating the oncogenic role of TRPM7 in cancer development and exploring its therapeutic potential as a target in combating this disease. Notably, TRPM7 fosters cancer invasion, metastasis, and uncontrolled cell proliferation, thereby perpetuating the expansion and reinforcement of these malignant entities. Furthermore, this review takes ovarian cancer as an example and summarizes the "dual-mode" regulatory role of TRPM7 in cancer. Within the domain of ovarian cancer, TRPM7 assumes the role of a harsh tyrant, firmly controlling the calcium ion signaling pathway and metabolic reprogramming pathways.

[Expression and clinical significance of miR-23a and metastasis suppressor 1 in colon carcinoma].

OBJECTIVE: To investigate the expression of miR-23a and metastasis suppressor 1 (MTSS1) and their clinical significance in colon carcinoma. METHODS: A total of 92 cases of colon carcinomas were collected with both the tumor and paired normal tissue samples for the study. The miR-23a targeting MTSS1 was evaluated by luciferase reporter vector. Cell invasion potential was evaluated by trans-well invasion assay. In-situ hybridization and immunohistochemistry were used to detect miR-23a and MTSS1 expression. RESULTS: MiR-23a downregulated the expression of MTSS protein and enhanced the invasiveness of colon carcinoma. The expression rates of miR-23a and MTSS1 were 87.0% (80/92) and 17.4% (16/92) in colon carcinoma cases, respectively (P < 0.01). The up-regulation of miR-23a expression was associated with an advanced clinical stage (P = 0.029) and depth of invasion (P = 0.000). The expression of miR-23a was higher in the tumors with lymph node metastasis than those without (P = 0.041). Down-regulation of MTSS1 expression was associated with an advanced clinical stage (P = 0.027) and depth of invasion (P = 0.017). The expression of MTSS1 was lower in the tumors with lymph node metastasis than those without (P = 0.009). The expression of miR-23a had significantly negative correlation with that of MTSS1 (r = -0.594, P = 0.013). CONCLUSIONS: MiR-23a expression promotes colon carcinoma cell growth, invasion and metastasis through inhibition of MTSS gene. Both the low expression of MTSS1 and high expression of miR-23a may serve as important biological markers for the malignant phenotypes of colon cancer, such as invasion and metastasis.

Circular RNA circKIF4A Sponges miR-375/1231 to Promote Bladder Cancer Progression by Upregulating NOTCH2 Expression.

Circular RNAs (circRNAs) have been found to be important mediators of many biological processes in the growth and metastasis of various cancers. However, the potential roles of most circRNAs in the progression of bladder cancer remain unclear. In this research, we investigate the role of circKIF4A (hsa_circ_0007255) in the development and progression of bladder cancer. Detected by qRT-PCR analysis, circKIF4A was significantly upregulated in bladder cancer tissues and cell lines. We conducted CCK-8, colony-formation, transwell and mouse xenograft assays to explore the function of circKIF4A in bladder cancer. Functionally, knockdown of circKIF4A inhibited the proliferation and colony-formation ability of bladder cancer cells. Migration and metastatic ability were dramatically decreased after transfection with small interfering RNA targeting circKIF4A in both in vitro and in vivo assays. Mechanically, luciferase reporter assays and RNA immunoprecipitation assays were carried out to elucidate the underlying molecular mechanism of circKIF4A. The results revealed that circKIF4A sponges miR-375/1231 to promote bladder cancer progression by upregulating NOTCH2. Generally, our research unveils the essential role of circKIF4A-miR-375/1231-NOTCH2 axis in bladder cancer progression possibly via the competing endogenous RNA mechanism.

Role of lncRNA and EZH2 Interaction/Regulatory Network in Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts and longer than 200 nucleotides. LncRNAs have been demonstrated to modulate gene expression at transcriptional, post-transcriptional, as well as epigenetic levels in lung cancer. Interestingly, compelling studies have revealed that lncRNAs participated in the EZH2 oncogenic regulatory network. EZH2 plays an important role in the initiation, progression and metastasis of cancer. On one hand, lncRNAs can directly bind to EZH2, recruit EZH2 to the promoter region of genes and repress their expression. On the other hand, lncRNAs can also serve as EZH2 effectors or regulators. In this review, we summarized the types of lncRNA-EZH2 interaction and regulatory network identified till date and discussed their influence on lung cancer. Better understanding regarding the interaction and regulatory network will provide new insights on lncRNA- or EZH2-based therapeutic development in lung cancer.

Diallyl disulfide inhibits the proliferation of HT-29 human colon cancer cells by inducing differentially expressed genes.

Diallyl disulfide (DADS), a sulfur compound derived from garlic, has been shown to have protective effects against colon carcinogenesis in several studies performed in rodent models. However, its molecular mechanism of action remains unclear. This study was designed to confirm the anti-proliferative activity of DADS and to screen for differentially expressed genes induced by DADS in human colon cancer cells with the aim of exploring its possible anticancer mechanisms. The anti-proliferative capability of DADS in the HT-29 human colon cancer cells was analyzed by MTT assays and flow cytometry. The differences in gene expression between DADS-treated (experimental group) and untreated (control group) HT-29 cells were identified using two-directional suppression subtractive hybridization (SSH). Semi-quantitative reverse transcription polymerase chain reaction (semi-RT-PCR) was selected to confirm the results obtained by SSH. Based on the results, a dose- and time-dependent growth inhibition was observed in the DADS-treated HT-29 cells. Forty-nine known genes and a new gene were found to be involved in the anti-proliferative effects of DADS by SSH analysis, and two cDNA libraries, DHDG and DHUG, containing both up- and down-regulated genes in colon tumor cells, were constructed. These genes were related to transduction, cell proliferation/growth/apoptosis and secreted/extracellular matrix proteins. Semi-RT-PCR results showed an expression pattern consistent with that of the SSH analysis. In conclusion, DADS showed anti-proliferative effects on colon cancer HT-29 cells, and DHDG and DHUG genes were found to be involved in this process. Further studies on the identification and description of these genes may allow a better understanding of the protective roles of DADS in colon carcinogenesis.

Stage-associated dynamic activity profile of transcription factors in nasopharyngeal carcinoma progression based on protein/DNA array analysis.

Transcription factors (TFs) are crucial modulators of gene regulation during the development and progression of tumors. We previously reported the activation of TFs in nasopharyngeal carcinoma (NPC) cell lines. In this study, we explored the activity profiles of TFs in Protein/DNA array data of a 12-tissue independent set and a 13-tissue pooled set of NPC that included different clinical stages. TFs associated with tumor progression were revealed using a generalized linear model-based regression analysis. Immunohistochemical analysis of clinical NPC samples was used to validate the results of array analysis. We identified 26 TFs that showed increased activities. Of these 26 TFs, 16 were correlated with clinical stages. Activity changes of AP2 and ATF/CREB were confirmed by electrophoretic mobility shift assay (EMSA), and increased expression of AP2α, ß, γ, ATF2, and ATF1 in nuclei of tumor cells was associated with clinical stages. In addition, the expressions of AP2α, ATF2, and ATF1 were correlated with those of their target genes (epithelia growth factor receptor (EGFR) and matrix metalloproteinase 2 (MMP-2), respectively). This study provides data and valuable clues that can be used to further investigate the laws of gene transcription regulation in NPC and to identify suitable targets for the development of TF-targeted antitumor agents.

Effect of diallyl disulfide on cell cycle arrest of human colon cancer SW480 cells.

BACKGROUND AND OBJECTIVE: Our previous study revealed that diallyl disulfide (DADS) significantly inhibited cell proliferation and induced cell cycle arrest at G(2)/M phase of human colon cancer SW480 cells. However, the molecular mechanism of cell cycle arrest remains unclear. This study was to investigate the role and the molecular mechanism of DADS in the induction of cell cycle arrest of human colon cancer cell line SW480. METHODS: Proliferation of SW480 cells after DADS treatment was measured by MTT assay and cell counting. Phase distribution of cell cycle was analyzed by flow cytometry. Expressions of PCNA, p53, p21(WAF1) and cyclin B1 were detected by immunohistochemistry and western blot. RESULTS: DADS (30-70 microg/mL) significantly inhibited proliferation and retarded the population doubling time of colonies in SW480 cells. Compared with the control group, SW480 cells were markedly accumulated at G(2)/M phase after the treatment with DADS (p < 0.05). Moreover, DADS remarkably decreased the protein contents of PCNA, p53 and cyclin B1, but increased the expression of p21(WAF1) in a time- and dose-dependent manner. CONCLUSION: DADS induces G(2)/M arrest in human colon cancer SW480 cells, probably through the downregulation of PCNA, p53 and cyclin B1 and upregulation of p21(WAF1).

[Inhibitory effect of diallyl disulfide on proliferation of human colon cancer cell line SW480 in nude mice].

BACKGROUND & OBJECTIVE: Diallyl disulfide (DADS) can inhibit the proliferation of various cancer cell lines in vitro, but little is known about its in vivo antitumor effect. This study was to investigate the inhibitory effect of DADS on the proliferation of human colon cancer cell line SW480 in nude mice. METHODS: After subcutaneous transplantation of SW480 cells in the back of nude mice, 5 mice received intraperitoneal injection of DADS (30 mg/kg), and 5 received intraperitoneal injection of normal saline as control. The body weight of nude mice and tumor growth were measured. The morphology of tumor was observed under optical microscope and electron microscope. The expression of proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry and morphometric quantitative analysis. Cell cycle distribution was analyzed by flow cytometry (FCM). RESULTS: The growth of transplanted tumor was inhibited markedly by DADS; the relative tumor growth rate (T/C%) was 49.85%. In DADS group, the cellular atypia and nucleus-cytoplasm ratio were decreased, intracytoplasm cellular organs were abundant, and retrograde alters and apoptotic bodies were manifested in some cells. The protein level of PCNA was significantly lower in DADS group than in control group (149.02+/-4.26 vs. 178.86+/-7.69, P<0.05). SW480 cells in DADS group were arrested in G2/M phase; the G2/M phase proportion was significantly higher in DADS group than in control group (38.6% vs. 18.8%, P<0.01). CONCLUSION: DADS has significant inhibitory effect on the proliferation of human colon cancer SW480 cells in nude mice and can arrest cell cycle in G2/M phase.

Diallyl disulfide suppresses growth of HL-60 cell through increasing histone acetylation and p21WAF1 expression in vivo and in vitro.

AIM: To examine the differentiation induction and growth inhibition of HL-60 cells by diallyl disulfide (DADS), and its relationship with the alterations of histone acetylation and p21(WAF1) expression in vitro and in vivo. METHODS: Differentiation was studied by nitroblue tetrazolium (NBT) reduction of HL-60 cell in vitro. HL-60 cells 5x10(6) were injected into the right side of the peritoneal cavity of severe combined immunodeficiency (SCID) mice. When the peritoneal neoplasms were detected, the SCID mice were randomly divided into 3 groups and received an ip injection of vehicle alone (NS), DADS or sodium butyrate (SB). The growth inhibition of peritoneal neoplasms induced by DADS was observed by a growth curve. The cycle distribution of HL-60 cells in SCID mice was monitored by flow cytometry. The expression of acetylated histone H3, H4 and p21(WAF1) were measured by Western blot. RESULTS: After treatment with DADS for 0-72 h, the NBT reduction ability of HL-60 cells increased in a time-dependent manner, compared with no treatment of HL-60 cells. In the HL-60 cells treated with DADS for 24 h, the expression of acetylated histone H3, H4, and p21(WAF1) increased obviously. After treatment with DADS, tumor growth was markedly suppressed. HL-60 cells from mice treated with DADS were blocked in the G1 phase, from 25.4% to 63.4%. The tumors from the mice treated with DADS showed an increase of acetylated histone H3, H4, and p21(WAF1). CONCLUSION: DADS could induce differentiation and inhibit the growth of HL-60 cells through increasing the expression of acetylated histone H3, H4, and p21(WAF1) in vitro and in vivo.

[Antitumor effect of diallyl disulfide on human gastric cancer MGC803 cells xenograft in nude mice].

BACKGROUND & OBJECTIVE: Diallyl disulfide (DADS) can inhibit growth of various cancer cell lines in vitro, but little is known about its in vivo antitumor effect. This study was designed to investigate effect of DADS on growth of human gastric carcinoma MGC803 cells xenograft in BALB/C nude mice. METHODS: MGC803 cells, with or without 1-day treatment of DADS (30 mg/L), were subcutaneously transplanted into the right axial regions of nude mice. The xenograft tumor growth in mice was observed after in vitro treatment or intraperitoneal injection of DADS. Proliferating cell nuclear antigen (PCNA) expression was detected by Western blot. RESULTS: No xenograft tumor was observed in the nude mice inoculated with DADS-treated MGC803 cells. When injected with 50, 100, and 200 mg/kg of DADS, the inhibition rate of tumor growth in the nude mice inoculated with untreated MGC803 cells were 27.8%, 66.1%, and 73.0%; the expression of PCNA was inhibited. CONCLUSION: DADS could suppress incidence of human gastric carcinoma xenograft in BALB/C nude mice, and inhibit growth of transplanted tumor.