Lessons from community participation in primary health care and water resource governance in South Africa: a narrative review.

BACKGROUND: In South Africa, community participation has been embraced through the development of progressive policies to address past inequities. However, limited information is available to understand community involvement in priority setting, planning and decision-making in the development and implementation of public services. OBJECTIVE: This narrative review aims to provide evidence on forms, extents, contexts and dynamics of community participation in primary health care (PHC) and water governance in South Africa and draw cross-cutting lessons. This paper focuses on health and water governance structures, such as health committees, Catchment Management Agencies (CMA), Water User Associations (WUAs), Irrigation Boards (IBs) and Community Management Forums (CMFs). METHODS: Articles were sourced from Medline (Ovid), EMBASE, Google Scholar, Web of Science, WHO Global Health Library, Global Health and Science Citation Index between 1994 and 2020 reporting on community participation in health and water governance in South Africa. Databases were searched using key terms to identify relevant research articles and grey literature. Twenty-one articles were included and analysed thematically. RESULTS: There is limited evidence on how health committees are functioning in all provinces in South Africa. Existing evidence shows that health committees are not functioning effectively due to lack of clarity on roles, autonomy, power, support, and capacity. There was slow progress in establishment of water governance structures, although these are autonomous and have mechanisms for democratic control, unlike health committees. Participation in CMAs/WUAs/IBs/CMFs is also not effective due to manipulation of spaces by elites, lack of capacity of previously disadvantaged individuals, inadequate incentives, and low commitment to the process by stakeholders. CONCLUSION: Power and authority in decision-making, resources and accountability are key for effective community participation of marginalized people. Practical guidance is urgently required on how mandated participatory governance structures can be sustained and linked to wider governance systems to improve service delivery.

PEG10 as an oncogene: expression regulatory mechanisms and role in tumor progression.

Cancer is a major public health problem as one of the leading causes of death worldwide. Deciphering the molecular regulation mechanisms of tumor progression can make way for tumor diagnosis and therapy. Paternally expressed gene 10 (PEG10), located on human chromosome 7q21.3, has turned out to be an oncogene implicated in the proliferation, apoptosis and metastasis of tumors. PEG10 has been found to be positively expressed in a variety of cancers with seemingly complex expression regulation mechanisms. In this review, we focus on the most vital factors influencing PEG10 expression and recapitulate some of the currently known and potential mechanisms of PEG10 affecting tumor progression, as understanding the molecular regulatory mechanisms of tumor progression can provide potential PEG10 related diagnosis and biomarker specific targeted therapies.

NHE1 has a notable role in metastasis and drug resistance of T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) represents a spectrum of hematological malignancies that affect human health. Metastasis and chemotherapeutic drug resistance are the primary causes of mortality in patients with T-ALL. Sodium-hydrogen antiporter 1 (NHE1) is established to serve a role in metastasis and drug resistance in numerous types of cancer; however, the function of NHE1 in T-ALL remains to be elucidated. Previously, the C-C-motif chemokine ligand 25 (CCL25) was identified to be involved in metastasis and drug resistance in the MOLT4 T-ALL cell line, as was the ezrin protein. The present study investigated the role of NHE1 in the metastasis of T-ALL using a Transwell assay and scanning electron microscopy, using MOLT4 cells as a model. The association between NHE1 and ezrin was assessed using laser scanning confocal microscopy. The effect of NHE1 on resistance to the chemotherapy drug doxorubicin (DOX) was also investigated using a cell viability and cytotoxicity assay. Expression of NHE1 increased following treatment with CCL25, accompanied by morphological changes in MOLT4 cells and the co-localization of NHE1 with ezrin. In addition, wild-type MOLT4 cells exhibited an increased polarization ability compared with NHE1- or ezrin-silenced cells. NHE1- or ezrin-silenced cells exhibited higher sensitivity to DOX compared with wild-type MOLT4 cells. In conclusion, the increased expression or activity of NHE1 may potentially be a poor prognostic indicator for human T-ALL.

Wnt5a and CCL25 promote adult T-cell acute lymphoblastic leukemia cell migration, invasion and metastasis.

Adult T-cell acute lymphoblastic leukemia (T-ALL) is a refractory leukemia. We previously showed that CCL25/CCR9 promotes T-ALL metastasis. In the present study, we assessed the effects of CCL25 on Wnt expression and the effects of Wnt5a and CCL25 on PI3K/Akt and RhoA activation. Transwell assays and mouse xenograft experiments were utilized to assess the effects of Wnt5a and CCL25 on MOLT4 cell invasion, migration and metastasis. The effects of Wnt5a on MOLT4 cell actin polarization and pseudopodium formation were examined using laser scanning confocal microscopy and scanning electron microscopy. CCL25 induced Wnt5a expression in MOLT4 cells by promoting protein kinase C (PKC) expression and activation. Wnt5a promoted MOLT4 cell migration, invasion, actin polarization, and lamellipodium and filopodia formation via PI3K/Akt-RhoA pathway activation. These effects were rescued by PI3K/Akt or RhoA knockdown or inhibition. Additionally, Wnt5a in cooperation with CCL25 promoted MOLT4 cell mouse liver metastasis and stimulated RhoA activation. These results show that CCL25/CCR9 upregulates Wnt5a by promoting PKC expression and activation in MOLT4 cells. This in turn promotes cell migration and invasion via PI3K/Akt-RhoA signaling, enhancing cell polarization and pseudopodium formation. These findings indicate that the PI3K/Akt-RhoA pathway is likely responsible for Wnt5a-induced adult T-ALL cell migration and invasion.

CXCR4 is involved in CD133-induced EMT in non-small cell lung cancer.

Metastasis is the major cause of death in patients with non-small cell lung cancer (NSCLC), and epithelial-mesenchymal transition (EMT) has been observed to be one of the key regulators of metastasis in certain cancers as it confers an invasive phenotype. CD133 is a widely used cancer stem cell (CSC) marker, and CD133-positive cancer cells are thought to be tumor-initiating cells with CSC characteristics, while CXCR4, a stromal-derived-factor-1 specific chemokine receptor, is highly expressed in NSCLC tissues and participates in cancer progression by regulating cell anti-apoptosis. We previously demonstrated that CXCR4 promotes NSCLC chemoresistance by upregulating CYP1B1, however, the relationship of CD133, CXCR4 and EMT processes in NSCLC metastasis are unclear. In this study, we detected a CD133 and CXCR4 high expression in tissue specimens from 64 NSCLC patients by immunohistochemistry, of which CD133 and CXCR4 were found to be positively associated with metastatic NSCLC patients. CD133 was found to promote NSCLC tumorigenesis and mediated the expression of CXCR4. Furthermore, CD133/CXCR4 co-expression was found to be an independent prognostic factor as shown by univariate and multivariate Cox regression analysis, and was observed to regulate the expression of EMT-related molecules and transcriptional factors in NSCLC. In addition, our results showed that E-cadherin and Vimentin were simultaneously downregulated and upregulated, in CD133+CXCR4+ A549 cells, respectively. While E-cadherin was upregulated and Vimentin was downregulated in metastatic NSCLC patients. Vimentin expression was also observed to have a positive correlation with CD133/CXCR4 co-expression in NSCLC patients and survival analysis results suggested that Vimentin high expression might be significantly associated with poor survival rates of the patients. Thus, these results suggest that the CD133/CXCR4/EMT axis may be a prognostic marker and may provide novel targets for combinational therapies in the treatment of NSCLC.

CXCR4 promotes cisplatin-resistance of non-small cell lung cancer in a CYP1B1-dependent manner.

Chemoresistance is the main cause of treatment failure and high mortality in advanced lung cancer. Cisplatin, an important chemotherapeutic agent for lung cancer, has been observed to show enormously reduced chemotherapeutic efficacy owing to the development of chemoresistance. CXCR4, a stromal-derived-factor-1 specific chemokine receptor, is highly expressed in non-small cell lung cancer (NSCLC) tissues and participates in cancer progression by regulating cell growth, apoptosis or invasion. In this study, we therefore investigated whether CXCR4 plays a role in the cisplatin associated resistance in NSCLC. We detected the expression of CXCR4 in tissue specimens from 64 NSCLC patients by immunohistochemistry. Cisplatin-resistant NSCLC cells A549/DDP and its parental A549 cells were employed in this study. RNA interference was performed to silence the CXCR4. The influence of CXCR4 on tumor cell chemoresistance, apoptosis and growth, as well as the relationship between CXCR4 and the expression of cytochrome p450 associated molecule CYP1B1 in NSCLC were evaluated. Finally, we found CXCR4 was significantly highly expressed in cisplatin-resistant NSCLC patients and the A549/DDP cell line. CXCR4 inhibition by siRNA reversed chemoresistance and decreased tumor cell proliferation. Bioinformatics analysis showed that the expression of CYP1B1 had a positive correlation with CXCR4, the CYP1B1 silencing significantly decreased CXCR4 expression levels and cisplatin resistance. Immunohistochemistry also verified that CYP1B1 was upregulated in NSCLC tissues of cisplatin-resistant patients. In conclusion, our results indicate that overexpression of CXCR4 in NSCLC promotes cisplatin resistance via CXCR4-mediated CYP1B1 upregulation. Thus, it can be used as a potential therapeutic target in NSCLC chemoresistance patients and be used as a clinical predictor of cisplatin response.

PEG10 promotes human breast cancer cell proliferation, migration and invasion.

Paternally expressed imprinted gene 10 (PEG10), derived from the Ty3/Gypsy family of retrotransposons, has been implicated as a genetic imprinted gene. Accumulating evidence suggests that PEG10 plays an important role in tumor growth in various cancers, including hepatocellular carcinoma, lung cancer and prostate cancer. However, the correlation between PEG10 and breast cancer remains unclear. In the present study, we evaluated and characterized the role of PEG10 in human breast cancer proliferation, cell cycle, clone formation, migration and invasion. The expression level of PEG10 was significantly elevated in breast cancer tissues and associated with distant metastasis and poor clinical outcome. Gene set enrichment analysis indicated that high expression of PEG10 could enrich cell cycle-related processes in breast cancer tissues. Ectopic overexpression of PEG10 in breast cancer cells enhanced cell proliferation, cell cycle, clone formation along with migration and invasion. Cell-to-cell junction molecule E-cadherin was downregulated and matrix degradation proteases MMP-1, MMP-2, MMP-9 were up-regulated after PEG10 overexpression. Our results demonstrated that PEG10 is a crucial oncogene and has prognostic value for breast cancer, which could be applied in breast cancer diagnosis and targeting therapy in future.

CCR9 in cancer: oncogenic role and therapeutic targeting.

Cancer is currently one of the leading causes of death worldwide and is one of the most challenging major public health problems. The main challenges faced by clinicians in the management and treatment of cancer mainly arise from difficulties in early diagnosis and the emergence of tumor chemoresistance and metastasis. The structures of chemokine receptor 9 (CCR9) and its specific ligand chemokine ligand 25 (CCL25) have been elucidated, and, interestingly, a number of studies have demonstrated that CCR9 is a potential tumor biomarker in diagnosis and therapy, as it has been found to be highly expressed in a wide range of cancers. This expression pattern suggests that CCR9 may participate in many important biological activities involved in cancer progression. Researchers have shown that CCR9 that has been activated by its specific ligand CCL25 can interact with many signaling pathways, especially those involved in tumor chemoresistance and metastasis. This review, therefore, focuses on CCR9 induction activity and summarizes what is currently known regarding its role in cancers and its potential application in tumor-targeted therapy.