Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Recently, ubiquitin-conjugating enzyme E2C (UBE2C) has been reported to be overexpressed in human ...cancers and act as a potential oncogene. However, little is known about the functional roles of UBE2C in HCC progression. In the present study, analysis of UBE2C mRNA expression in The Cancer Genome Atlas (TCGA) dataset reveals that significantly higher UBE2C mRNA levels was found in HCC tissues and associated with higher HCC grade. Elevated UBE2C mRNA levels in HCC indicated worsened survival probabilities. Through performing loss-of-function assays, we demonstrated that knockdown of UBE2C expression obviously suppressed proliferation, migration, and invasion of HCC cells
Moreover, HCC cells with UBE2C knockdown showed higher sensitivity for the treatment of chemotherapeutic drug, including adriamycin (ADR) and 5-fluorouracil (5-FU). Silencing of UBE2C also increased the sensitivity of HCC cells to sorafenib, an approved treatment for patients with advanced-stage HCC. Our findings strongly suggest that UBE2C emerges as a marker for prognosis in HCC, and blocking UBE2C may be a novel strategy for HCC therapies.
Many studies have reported on laterally spreading tumors (LSTs), but systematic reviews of the data to determine their risk of containing submucosal invasion (SMI) are lacking. We systematically ...screened and analyzed the available literature to provide a more solid basis for evidence-based treatment.
We conducted a systematic search in PubMed, Embase, the Cochrane Library, and Scopus for published articles until July 2017. We estimated pooled prevalence or odds ratios (ORs) with 95 % confidence intervals (CIs), using random-effects models. We classified endoscopic subtypes into granular LST, which comprises the homogeneous and nodular mixed subtypes, and non-granular LST, which comprises the flat elevated and pseudodepressed subtypes.
We identified 2949 studies, of which 48 were included. Overall, 8.5 % (95 %CI 6.5 % - 10.5 %) of LSTs contained SMI. The risk of SMI differed among the LST subtypes: 31.6 % in non-granular pseudodepressed LSTs (95 %CI 19.8 % - 43.4 %), 10.5 % in granular nodular mixed LSTs (95 %CI 5.9 % - 15.1 %), 4.9 % in non-granular flat elevated LSTs (95 %CI 2.1 % - 7.8 %), and 0.5 % in granular homogenous LSTs (95 %CI 0.1 % - 1.0 %). SMI was more common in distally rather than in proximally located LSTs (OR 2.50, 95 %CI 1.24 - 5.02). The proportion of SMI increased with lesion size (10 - 19 mm, 4.6 %; 20 - 29 mm, 9.2 %; ≥ 30 mm, 16.5 %). The pooled prevalence of patients with one or more LSTs in the general colonoscopy population was 0.8 % (95 %CI 0.6 % - 1.1 %).
The majority of LSTs are non-invasive at the time of colonoscopic detection and can be treated with (piecemeal) endoscopic mucosal resection. Pretreatment diagnosis of endoscopic subtype, specifying areas of concern (nodule or depression), determines those LSTs at highest risk of containing SMI, where en bloc resection is the preferred therapy.
Several studies have shown that tRNAs can be enzymatically cleaved to generate distinct classes of tRNA-derived fragments (tRF). Here, we report that tRF/miR-1280, a 17-bp fragment derived from tRNA
...and pre-miRNA, influences Notch signaling pathways that support the function of cancer stem-like cells (CSC) in colorectal cancer progression. tRF/miR-1280 expression was decreased in human specimens of colorectal cancer. Ectopic expression of tRF/miR-1280 reduced cell proliferation and colony formation, whereas its suppression reversed these effects. Mechanistic investigations implicated the Notch ligand JAG2 as a direct target of tRF/miR-1280 binding through which it reduced tumor formation and metastasis. Notably, tRF/miR-1280-mediated inactivation of Notch signaling suppressed CSC phenotypes, including by direct transcriptional repression of the Gata1/3 and miR-200b genes. These results were consistent with findings of decreased levels of miR-200b and elevated levels of JAG2, Gata1, Gata3, Zeb1, and Suz12 in colorectal cancer tissue specimens. Taken together, our results established that tRF/miR-1280 suppresses colorectal cancer growth and metastasis by repressing Notch signaling pathways that support CSC phenotypes. Furthermore, they provide evidence that functionally active miRNA can be derived from tRNA, offering potential biomarker and therapeutic uses.
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Exosomes are key mediators of intercellular communication and play a role in the pathogenesis and progression of cancer. Exosomes in circulating body fluids serve as molecular markers for cancer ...diagnosis. This study aimed to investigate the role of exosomal microRNA (miR)-1910-3p in breast cancer and determine its clinical diagnostic value. MiR-1910-3p promoted proliferation and migration of breast cancer cells in vitro and in vivo. In vitro, exosomes enriched in miR-1910-3p transferred miR-1910-3p to mammary epithelial cells and breast cancer cells, promoting proliferation and migration, inhibiting apoptosis, and inducing autophagy. In vivo, exosomes enriched in miR-1910-3p promoted the proliferation and migration of breast cancer cells. MiR-1910-3p downregulated myotubularin-related protein 3, activated the NF-κB and wnt/β-catenin signaling pathway, and promoted breast cancer progression. Serum miR-1910-3p in exosomes was an effective diagnostic marker that improved the sensitivity of breast cancer diagnosis when used in combination with the traditional tumor marker CA153. In conclusion, breast cancer cell-derived exosomes promoted the growth, metastasis, and autophagy of breast cancer cells by transferring miR-1910-3p. MiR-1910-3p in serum exosomes may serve as a novel molecular marker for breast cancer diagnosis.
•Exosome miR-1910-3p promoted proliferation and migration of breast cancer cells in vitro and in vivo.•Exosomes transferred miR-1910-3p, promoting proliferation and migration, and inducing autophagy in breast cancer.•MiR-1910-3p downregulated MTMR3, activated the NF-κB signaling pathway, and promoted breast cancer progression.•Serum miR-1910-3p in exosomes was an effective diagnostic marker that improved the sensitivity of breast cancer diagnosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The metastatic dissemination and underlying mechanisms of clear cell renal cell carcinoma (ccRCC) remain insufficiently understood. In this study, we identified the essential role of KLF2 in ...suppressing the metastasis of ccRCC. Downregulation of KLF2 detected by immunohistochemistry in primary metastatic ccRCC was remarkably related to poor clinical outcomes. Overexpression of KLF2 in vitro inhibited growth, migration and invasion of RCC cells. Analysis of clinical specimens revealed that there is a close correlation between KLF2 and GPX4 in ccRCC. Mechanistically, KLF2 deficiency is sufficient to inhibit ferroptosis on account of the impairment of transcriptional repression of GPX4 and thus promotes the migration and invasion of RCC cells. Reverting KLF2 expression in vivo decreased pulmonary metastatic lesions and prolonged life span of mice, whereas GPX4 overexpression reversed these properties. Overall, our results established a novel critical pathway that drives human ccRCC invasion and metastasis, which could be a promising target regarding to the therapies of advanced ccRCC in the clinic.
•KLF2 is downregulated in primary metastatic ccRCC tissues compared with non-metastatic tissues.•Overexpression of KLF2 inhibits ccRCC cells migration and invasion in vitro and metastasis in vivo.•KLF2 promotes ferroptosis to inhibit metastasis of ccRCC via suppression of GPX4.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The standard treatment for high-grade serous ovarian cancer is primary debulking surgery followed by chemotherapy. The extent of metastasis and invasive potential of lesions can influence the outcome ...of these primary surgeries. Here, we explored the underlying mechanisms that could increase metastatic potential in ovarian cancer. We discovered that FABP4 (fatty acid binding protein) can substantially increase the metastatic potential of cancer cells. We also found that miR-409-3p regulates FABP4 in ovarian cancer cells and that hypoxia decreases miR-409-3p levels. Treatment with DOPC nanoliposomes containing either miR-409-3p mimic or FABP4 siRNA inhibited tumor progression in mouse models. With RPPA and metabolite arrays, we found that FABP4 regulates pathways associated with metastasis and affects metabolic pathways in ovarian cancer cells. Collectively, these findings demonstrate that FABP4 is functionally responsible for aggressive patterns of disease that likely contribute to poor prognosis in ovarian cancer.
Circular RNAs (circRNAs) are a class of covalently closed non-coding RNAs and are widely involved in various cancers including colorectal cancer (CRC). Circular RNA PVT1 (circPVT1) was reported in ...several malignancies but the role it plays in CRC remains unclear. In our current research, we focused on the expression and function of circPVT1) works in CRC. We found that circPVT1 was upregulated in CRC. Also, we illustrated that the upregulated circPVT1 was closely correlated with poor prognosis and bad clinicopathological features of patients with CRC. Through a loss of function experiment, we showed that a downregulation of circPVT1 suppressed CRC cells metastasis. Through online prediction, we found that circPVT1 had a microRNA response element (MRE) for miR-145. Additionally, we demonstrated that miR-145 was downregulated in CRC. Even further, we showed that miR-145 was involved in circPVT1 mediated facilitation of CRC metastasis. In a further mechanical study, we demonstrated that circPVT1 could target miR-145. Lastly, we revealed that the metastasis-promoting role of circPVT1 in CRC was partially achieved via miR-145 sponging.
In brief, the findings of the present study illustrated that circPVT1, working as an oncogene, promotes metastasis via miR-145 sponging in CRC. CircPVT1/miR-145 axial might be a novel point in targeting treatment of CRC.
Circular RNA PVT1 (circPVT1), is upregulated and correlates with poor clinicopathological features in patients with CRC.CircPVT1, working as an oncogene, promotes migration and invasion in CRC cells HT29 and LOVO.MiR-145 was downregulated in CRC and was involved in circPVT1 mediated promotion of migration/invasion in CRC cells.CircPVT1 promoted CRC cells migration/invasion via miR-145 sponging.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background & Aims The roles of alternatively activated (M2) macrophages on pro-tumour phenotypes have been well documented in many cancers except hepatocellular carcinoma (HCC). Considering their ...close relationship with chronic tissue injuries as well as enhanced tumour invasiveness and growth, we aimed to investigate the direct effects of M2 macrophages on HCC. Methods M2 macrophages in 95 HCC clinical specimens were quantified using immunohistochemistry and quantitative PCR. The pro-tumour functions and the underlying molecular mechanisms of M2 macrophages in HCC were investigated in vivo and in an in vitro co-culture system. Results In the clinical study, high M2-specific CD163 (hazard ratio = 2.693; p = 0.043) and scavenger receptor A (hazard ratio = 3.563; p = 0.044) levels indicated poor prognosis and correlated with increased tumour nodules and venous infiltration in HCC patients. In an orthotopic model, the liver tumour volume was increased 3.26-fold (1.27 cm3 ± 0.36) after M2 macrophage injection compared with the control (0.39 cm3 ± 0.05) ( p = 0.032). An increased rate of lung metastasis was also found in the treatment group. In vitro , co-cultivation with M2 macrophages elevated the number of HCC cells (MHCC97L) and migration events by 1.3-fold and 3.2-fold, respectively ( p <0.05). Strongly induced by MHCC97L, M2 macrophage-derived CCL22 was proven to enhance tumour migration capacities and correlate with venous infiltration in HCC patients. Increased epithelial-mesenchymal transition (EMT) via Snail activation in MHCC97L was found to be promoted by M2 macrophages and CCL22. Conclusions M2 macrophages contribute to poor prognosis in HCC and promote tumour invasiveness through CCL22-induced EMT.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Macrophages within the tumor microenvironment facilitate angiogenesis and extracellular-matrix breakdown and remodeling and promote tumor cell motility. Recent studies reveal that direct ...communication between macrophages and tumor cells leads to invasion and egress of tumor cells into the blood vessels (intravasation). Thus, macrophages are at the center of the invasion microenvironment and are an important drug target for cancer therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Alterations in tumour metabolism and acid/base regulation result in the formation of a hostile environment, which fosters tumour growth and metastasis. Acid/base homoeostasis in cancer cells is ...governed by the concerted interplay between carbonic anhydrases (CAs) and various transport proteins, which either mediate proton extrusion or the shuttling of acid/base equivalents, such as bicarbonate and lactate, across the cell membrane. Accumulating evidence suggests that some of these transporters interact both directly and functionally with CAIX to form a protein complex coined the 'transport metabolon'. Transport metabolons formed between bicarbonate transporters and CAIX require CA catalytic activity and have a function in cancer cell migration and invasion. Another type of transport metabolon is formed by CAIX and monocarboxylate transporters. In this complex, CAIX functions as a proton antenna for the transporter, which drives the export of lactate and protons from the cell. Since CAIX is almost exclusively expressed in cancer cells, these transport metabolons might serve as promising targets to interfere with tumour pH regulation and energy metabolism. This review provides an overview of the current state of research on the function of CAIX in tumour acid/base transport and discusses how CAIX transport metabolons could be exploited in modern cancer therapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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