Moxidectin (MOX), a broad‑spectrum antiparasitic agent, belongs to the milbemycin family and is similar to avermectins in terms of its chemical structure. Previous research has revealed that milbemycins, including MOX, may potentially function as effective multidrug resistance agents. In the present study, the impact of MOX on the viability of glioma cells was examined by MTT and colony formation assay, and the molecular mechanisms underlying MOX‑mediated glioma cell apoptosis were explored by using flow cytometry and apoptosis rates. The results demonstrated that MOX exerts an inhibitory effect on glioma cell viability and colony formations in vitro and xenograft growth in vivo and is not active against normal cells. Additionally, as shown by western blot assay, it was demonstrated that MOX arrests the cell cycle at the G0/G1 phase by downregulating the expression levels of cyclin‑dependent kinase (CDK)2, CDK4, CDK6, cyclin D1 and cyclin E. Furthermore, it was revealed that MOX is able to induce cell apoptosis by increasing the Bcl‑2‑associated X protein/B‑cell lymphoma 2 ratio and activating the caspase‑3/‑9 cascade. In conclusion, these results suggest that MOX may inhibit the viability of glioma cells by inducing cell apoptosis and cell cycle arrest, and may be able to function as a potent and promising agent in the treatment of glioma.

Dysregulation of the cell cycle contributes to tumor progression. Cell division cycle‑associated 3 (CDCA3) is a known trigger of mitotic entry and has been demonstrated to be constitutively upregulated in tumors. It is therefore associated with carcinogenic properties reported in various cancers. However, the role of CDCA3 in prostate cancer is unclear. In the present study, western blotting and analysis of gene expression profiling datasets determined that CDCA3 expression was upregulated in prostate cancer and was associated with a poor prognosis. CDCA3 knockdown in DU145 and PC‑3 cells led to decreased cell proliferation and increased apoptosis, with increased protein expression levels of cleaved‑caspase3. Further experiments demonstrated that downregulated CDCA3 expression levels induced G0/G1 phase arrest, which was attributed to increased p21 protein expression levels and decreased cyclin D1 expression levels via the regulation of NF‑κB signaling proteins (NFκB‑p105/p50, IKKα/β, and pho‑NFκB‑p65). In conclusion, these results indicated that CDCA3 may serve a crucial role in prostate cancer and consequently, CDCA3 knockdown may be used as a potential therapeutic target.

Cyclin‑dependent kinase 5 regulatory subunit‑​associated protein 3 (CDK5RAP3 or C53) is involved in the development of various types of tumor, and alternative splicing of C53 results in numerous transcription variants that encode different isoforms. The present study aimed to clone human C53 isoform d (IC53d) and explore its role in the proliferation of gastric cancer cells. Reverse transcription‑quantitative polymerase chain reaction was used to detect the expression levels of IC53d in 80 primary gastric adenocarcinoma tissues and adjacent normal tissues. In addition, the association between IC53d and clinicopathological parameters was determined. Gastric cancer cell lines stably overexpressing IC53d were established to observe its effects on cell proliferation, invasion and migration, and on in vivo tumorigenicity, and the mechanism of action was explored. The results of the presen study demonstrated that IC53d was upregulated in gastric cancer tissues and was associated with tumor T‑stage. Furthermore, overexpression of IC53d promoted the proliferation, colony formation and G1/S phase transition of gastric cancer cells, leading to enhancement of tumorigenesis in vitro and in vivo. Overexpression of IC53d also promoted phosphorylation of protein kinase B (AKT) and glycogen synthase kinase 3β (GSK3β), which increased the expression of cyclin D1. In addition, high cyclin D1 expression was associated with a significantly worse prognosis for patients compared with in patients with low cyclin D1 expression. These results indicated that IC53d may promote the phosphorylation of AKT and GSK3β, which in turn may increase cyclin D1 expression, enhancing G1/S phase transition, accelerating cell cycle progression, promoting the proliferation of gastric cancer cells, and inducing a poor prognosis in patients with gastric cancer.

Increasing evidence has indicated the roles of sirtuin 7 (SIRT7) in numerous human cancers. However, the effects and the clinical significance of SIRT7 in human lung cancer is largely unknown. The present research demonstrated that SIRT7 was increased in human lung cancer tumor tissues. SIRT7 upregulation was associated with clinicopathological characteristics of lung cancer malignancy including positive lymph node metastasis, high pathologic stage and large tumor size. SIRT7 was also upregulated in human non‑small cell lung cancer (NSCLC) cell lines. Furthermore SIRT7‑overexpressed A549 (A549‑SIRT7) and SIRT7‑knocked down H292 (H292‑shSIRT7) human NSCLC cell lines were established. Using these NSCLC cells and xenograft mouse models, it was revealed that SIRT7 overexpression markedly promoted growth and G1 to S cell cycle phase transition as well as migration, invasion and distant lung metastasis in A549 NSCLC cells, whereas SIRT7 knockdown suppressed these processes in H292 NSCLC cells. Mechanistically, in A549 NSCLC cells, SIRT7 overexpression significantly activated not only protein kinase B (AKT) signaling but also extracellular signal‑regulated kinase 1/2 (ERK1/2) signaling. SIRT7 overexpression also significantly downregulated cyclin‑dependent kinase (CDK) inhibitors including p21 and p27 as well as upregulated cyclins including cyclin D1 and cyclin E1, and CDKs including CDK2 and CDK4. Notably, the epithelial‑mesenchymal transition (EMT) process of A549 NSCLC cells was facilitated by SIRT7 overexpression, as evidenced by E‑cadherin epithelial marker downregulation and mesenchymal markers (N‑cadherin, vimentin, Snail and Slug) upregulation. In addition, SIRT7 knockdown in H292 NSCLC cells exhibited the opposite regulatory effects. Moreover, inhibition of AKT signaling abated the promoting effects of SIRT7 in NSCLC cell proliferation and EMT progression. The present data indicated that SIRT7 accelerated human NSCLC cell growth and metastasis possibly by promotion of G1 to S‑phase transition and EMT through modulation of the expression of G1‑phase checkpoint molecules and EMT markers as well as activation of AKT and ERK1/2 signaling. SIRT7 could be an innovative potential target for human NSCLC therapy.

Lung cancer (LC) and pancreatic cancer (PC) are the first and fourth leading causes of cancer‑related deaths in the US. Deregulated cell cycle progression is the cornerstone for rapid cell proliferation, tumor development, and progression. Here, we provide evidence that a novel combinatorial miR treatment inhibits cell cycle progression at two phase transitions, through their activity on the CDK4 and CDK1 genes. Following transfection with miR‑143 and miR‑506, we analyzed the differential gene expression of CDK4 and CDK1, using qPCR or western blot analysis, and evaluated cell cycle inhibition, apoptosis and cytotoxicity. The combinatorial miR‑143/506 treatment downregulated CDK4 and CDK1 levels, and induced apoptosis in LC cells, while sparing normal lung fibroblasts. Moreover, the combinatorial miR treatment demonstrated a comparable activity to clinically tested cell cycle inhibitors in inhibiting cell cycle progression, by presenting substantial inhibition at the G1/S and G2/M cell cycle transitions. More importantly, the miR‑143/506 treatment presented a broader application, effectively downregulating CDK1 and CDK4 levels, and reducing cell growth in PC cells. These findings suggest that the miR‑143/506 combination acts as a promising approach to inhibit cell cycle progression for cancer treatment with minimal toxicity to normal cells.

MicroRNA (miR)‑181a is a member of the miR‑181 family that serves a key role in the pathogenesis of various cancer types. The present study aimed to investigate the interaction between miR‑181a and Ras association domain family protein1 isoform A (RASSF1A), and their roles in gastric carcinogenesis. The interaction between miR‑181a and RASSF1A was assessed in cell lines and cancer tissues. The direct binding of miR‑181a and RASSF1A was identified using a luciferase reporting gene system. The effects of miR‑181a and RASSF1A on gastric cancer cell growth, cell cycle and apoptosis were assessed with a Cell Counting Kit‑8 assay and flow cytometry. The effects of miR‑181a on cell division cycle 25A (CDC25A), cyclin A2, cyclin D1, p21, Bcl‑2‑associated X protein (Bax) and B‑cell lymphoma‑2 (Bcl‑2) protein levels were assessed in gastric cancer cell lines. miR‑181a directly interacted with the 3'‑untranslated region of RASSF1A and downregulated RASSF1A protein expression. In tissues from patients with gastric cancer, the miR‑181a level was significantly higher in the tumor tissues and was negatively correlated with the RASSF1A protein level. RASSF1A suppressed gastric cancer cell proliferation and G1/S transition, and promoted apoptosis; whereas miR‑181a promoted cancer cell proliferation and G1/S transition, and suppressed apoptosis. RASSF1A knockdown attenuated the effects of miR‑181a downregulation on cell proliferation and apoptosis. Furthermore, miR‑181a upregulated CDC25A, cyclin A2 and Bcl‑2, and downregulated Bax protein expression in gastric cancer cell lines. These data indicate that miR‑181a promotes gastric carcinogenesis, possibly through a direct interaction with RASSF1A.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third leading cause of cancer-related death. Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB) that might inhibit cancer cell proliferation, but the mechanisms through which telmisartan affects various cancers remain unknown. The aim of the present study was to evaluate the effects of telmisartan on human HCC and to assess the expression of microRNAs (miRNAs). We studied the effects of telmisartan on HCC cells using the HLF, HLE, HepG2, HuH-7 and PLC/PRF/5 cell lines. In our experiments, telmisartan inhibited the proliferation of HLF, HLE and HepG2 cells, which represent poorly differentiated types of HCC cells. However, HuH-7 and PLC/PRF/5 cells, which represent well-differentiated types of HCC cells, were not sensitive to telmisartan. Telmisartan induced G0/G1 cell cycle arrest of HLF cells by inhibiting the G0-to-G1 cell cycle transition. This blockade was accompanied by a marked decrease in the levels of cyclin D1, cyclin E and other cell cycle-related proteins. Notably, the activity of the AMP-activated protein kinase (AMPK) pathway was increased, and the mammalian target of rapamycin (mTOR) pathway was inhibited by telmisartan treatment. Additionally, telmisartan increased the level of caspase-cleaved cytokeratin 18 (cCK18), partially contributed to the induction of apoptosis in HLF cells and reduced the phosphorylation of ErbB3 in HLF cells. Furthermore, miRNA expression was markedly altered by telmisartan in vitro. In conclusion, telmisartan inhibits human HCC cell proliferation by inducing cell cycle arrest.

Brain‑derived neurotrophic factor (BDNF) is known as one of the members of the neurotropin family. BDNF‑induced activation of its receptor tyrosine kinase B (TrkB) is associated with anoikis tolerance, tumor progression and poor prognosis in many types of malignancy. However, to the best of our knowledge, there are no reports describing the contribution of the BDNF/TrkB axis to cervical cancer. BDNF and TrKB expression in cervical cancer (CC) tissues and adjacent normal tissues from 87 patients were analyzed by immunohistochemistry, western blot analysis and quantitative PCR assays and the results showed that they were significantly higher in cancer tissues than that in normal adjacent tissues, respectively. Higher expression rates of BDNF and TrKB were observed in stage IIB or higher and BDNF expression was positively associated with lymph node metastasis. Notably, a high expression of TrKB may be contributed to poor survival time, which confirmed by Kaplan‑Meier analysis. Compared to the corresponding CC cell lines, HeLa, SiHa, CASKI, C4‑1 and C‑33a, BDNF and TrKB expression was enhanced in anoikis‑like apoptotic tolerance (AAT), a cell model established from cervical cancer cell lines. AAT cells showed a higher proliferation activity compared with CC cell lines, which was confirmed by a shorter G0/G1 phase, elevated cyclin A, cyclin D1 and c‑myc, decreased caspase‑3 and Bax, and increased Bcl‑2. By contrast, the knockdown of TrKB expression reversed these changes in AAT cells, induced G0/G1 arrest and suppressed proliferation activity. The results of the present study show that PI3K/Akt signaling is involved in the BDNF/TrKB‑induced proliferation of AAT cells in cervical cancer. These findings indicate that BDNF/TrKB pathway is a potential target for the treatment of cervical cancer.

Endometrial cancer (EC) is the most common gynecological cancer, and one of the most important causes of cancer‑related deaths in women worldwide. The long‑term survival rate is lower in advanced‑stage and recurrent EC, therefore it is important to identify new anticancer drugs. Garcinol, a polyisoprenylated benzophenone, is a promising anticancer drug for various cancer types but its effects on EC remain unclear. To investigate the anticancer effects of garcinol on EC, cell proliferation and cell cycle were assessed by real‑time cell proliferation, cell counting, and colony formation assays, flow cytometric analysis, and 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation assay, in EC Ishikawa (ISH) and HEC‑1B cell lines. Western blotting was used to evaluate the expression of cell cycle‑related protein cyclins, cyclin‑dependent kinase and tumor suppression proteins. Garcinol inhibited ISH and HEC‑1B cell proliferation in a dose‑dependent manner, and induced ISH and HEC‑1B cell cycle arrest at the G1 phase and G2/M phase, respectively, and decreased the S phase and DNA synthesis in these two cell lines. Following garcinol treatment the expression levels of p53 and p21 were increased, while the expression levels of CDK2, CDK4, cyclin D1 and cyclin B1 were gradually decreased in a dose‑dependent manner in both ISH and HEC‑1B cells. In addition, the expression levels of phosphorylated c‑JUN N‑terminal kinase (JNK) and p‑c‑JUN were significantly increased in both types of cells. Collectively, garcinol can induce EC cell cycle arrest and may be a promising candidate for EC chemotherapy.

Aspirin, a nonsteroidal anti‑inflammatory drug (NSAID), is known to inhibit cell proliferation in a variety of cancers. However, the underlying mechanism of this inhibition remains unknown. We investigated the effects of aspirin on hepatocellular carcinoma (HCC) cells using in vitro and in vivo models. Six HCC cell lines and a liver cancer cell line including Huh‑7 were used in assays that evaluated cell proliferation, cell cycle, and apoptosis. Flow cytometry, enzyme‑linked immunosorbent assay (ELISA), western blot analysis, and phosphorylated receptor tyrosine kinase array were used to evaluate the effects of aspirin on the cells, and microRNAs (miRNAs) were analyzed by a miRNA array chip. The results were validated in vivo using a nude mouse model of Huh‑7‑xenografted tumors. Our results showed that aspirin exhibited an antiproliferative effect on all cell lines. Moreover, aspirin induced G0/G1 cell cycle arrest and modulated the levels of cell cycle‑related molecules such as cyclin E, cyclin D1, and cyclin‑dependent kinase 2 (Cdk2). In addition, aspirin upregulated the levels of caspase‑cleaved cytokeratin 18, increased the proportion of early apoptotic cells, decreased the levels of clusterin and heat shock protein 70 (HSP 70), upregulated the levels of miRNA‑137 and inhibited epidermal growth factor receptor (EGFR) activation. In addition, we observed that aspirin suppressed cell proliferation partially through the miRNA‑137/EGFR pathway. Our in vivo results showed that aspirin reduced the growth of xenograft tumors in nude mice. In conclusion, aspirin was able to inhibit the growth of HCC cells by cell cycle arrest, apoptosis, and alteration of miRNA levels in in vitro and in vivo models.

CXC chemokine receptor 7 (CXCR7) is frequently overexpressed in cancer and plays a significant role in tumor growth and metastasis. Consequently, inhibition of CXCR7 is important for treatment strategies. However, little is known concerning the biological role of CXCR7 and its underlying mechanisms in head and neck squamous cell carcinoma (HNSCC). The present study investigated the role of CXCR7 in HNSCC, as well as the effects of decursin, a pyranocoumarin compound isolated from Angelica gigas Nakai, on CXCR7 and its downstream signaling. Expression levels of CXCR7 in HNSCC cells were examined using flow cytometry, reverse transcriptase PCR, western blot analysis, and immunofluorescence. The effects of CXCR7 on cell proliferation, migration, and invasion were studied using CCK‑8, gap closure, and transwell assays. The results revealed that decursin significantly reduced CXCR7 expression and inhibited cell proliferation, migration, and invasion of human HNSCC cell lines. In addition, decursin induced G0/G1 cell cycle arrest in CXCR7‑overexpressing cells and decreased the levels of cyclin A, cyclin E, and CDK2. Furthermore, CXCR7 promoted cancer progression via the STAT3/c‑Myc pathway in HNSCC; suppression of CXCR7 with decursin prevented this effect. These results suggest that CXCR7 promotes cancer progression through the STAT3/c‑Myc pathway and that the natural compound decursin targets CXCR7 and may be valuable in the treatment of HNSCC.

Glioblastoma (GBM) is the most common type of primary central nervous system tumor in adults, which has high mortality and morbidity rates, and short survival time, namely <15 months after the diagnosis and application of standard therapy, which includes surgery, radiation therapy and chemotherapy; thus, novel therapeutic strategies are imperative. The activation of the PI3K/AKT signaling pathway plays an important role in GBM. In the present study, U87 and U251 GBM cells were treated with the PI3K/mTORC1/2 inhibitor PQR309, and its effect on glioma cells was investigated. Cell Counting Kit‑8 assay, 5‑ethynyl‑2'‑deoxyuridine and colony formation assays revealed dose‑ and time‑dependent cytotoxicity in glioma cells that were treated with PQR309. Flow cytometry and western blotting revealed that PQR309 can significantly induce tumor cell apoptosis and arrest the cell cycle in the G1 phase. Furthermore, the expression levels of AKT, phosphorylated (p)‑AKT, Bcl‑2, Bcl‑xL, Bad, Bax, cyclin D1, cleaved caspase‑3, MMP‑9 and MMP‑2 were altered. In addition, the migration and invasion of glioma cells, as detected by wound healing, migration and Transwell invasion assays, exhibited a marked suppression after treating the cells with PQR309. These results indicated that PQR309 exerts an antitumor effect by inhibiting proliferation, inducing apoptosis, inducing G1 cell cycle arrest, and inhibiting invasion and migration in human glioma cells. The present study provides evidence supportive of further development of PQR309 for adjuvant therapy of GBM.

Lung squamous cell carcinoma (LSCC) is a highly heterogeneous malignancy with high mortality and few therapeutic options. Licochalcone A (LCA, PubChem ID: 5318998) is a chalcone extracted from licorice and possesses anticancer and anti‑inflammatory activities. The present study aimed to elucidate the anticancer effect of LCA on LSCC and explore the conceivable molecular mechanism. MTT assay revealed that LCA significantly inhibited the proliferation of LSCC cells with less cytotoxicity towards human bronchial epithelial cells. 5‑ethynyl‑2'‑deoxyuridine (EdU) assay demonstrated that LCA could reduce the proliferation rate of LSCC cells. The flow cytometric assays indicated that LCA increased the cell number of the G1 phase and induced the apoptosis of LSCC cells. LCA downregulated the protein expression of cyclin D1, cyclin E, CDK2 and CDK4. Meanwhile, LCA increased the expression level of Bax, cleaved poly(ADP‑ribose)polymerase‑1 (PARP1) and caspase 3, as well as downregulated the level of Bcl‑2. Proteomics assay demonstrated that LCA exerted its antitumor effects via inhibiting mitogen‑activated protein kinase (MAPK) signaling pathways and the expression of F‑box protein 5 (FBXO5). Western blot analysis showed that LCA decreased the expression of p‑ERK1/2, p‑p38MAPK and FBXO5. In the xenograft tumors of LSCC, LCA significantly inhibited the volumes and weight of tumors in nude mice with little toxicity in vital organs. Therefore, the present study demonstrated that LCA effectively inhibited cell proliferation and induced apoptosis in vitro, and suppressed xenograft tumor growth in vivo. LCA may serve as a future therapeutic candidate of LSCC.

Diffuse large B‑cell lymphoma (DLBCL) is one of the most common types of lymphoma. Calponin 3 (CNN3) is a thin filament‑associated protein previously known to regulate smooth muscle contraction. Recent evidence illustrates its involvement in carcinogenesis; however, its roles in DLBCL remain unknown. CNN3 was found to be highly expressed in DLBCL specimens according to the online Gene Expression Profiling Interactive Analysis data. The aim of the present study was to investigate the roles of CNN3 in the progression of DLBCL. In vitro, the ectopic expression of CNN3 promoted the proliferation and G1/S transition of DLBCL cells, while its silencing led to opposite alterations. A similar tumor‑promoting role of CNN3 was also demonstrated by injecting nude mice with DLBCL cells over‑ or underexpressing CNN3. The results of dual‑luciferase reporter and chromatin immunoprecipitation assays revealed that forkhead box O3 (FOXO3), a known tumor suppressor in DLBCL, bound to the CNN3 promoter at ‑1955/‑1948 and ‑1190/‑1183, and suppressed the transcription of CNN3. The alterations induced by FOXO3 were partly blocked by CNN3 overexpression. On the whole, the present study demonstrates that CNN3, whose transcriptional activity is negatively regulated by FOXO3, contributes to the malignant behavior of DLBCL cells. The findings of the present study may provide novel diagnostic or therapeutic insight for DLBCL in clinical practice.

Solanum nigrum L. (Longkui) is one the most widely used anticancer herbs in traditional Chinese medicine. α‑Solanine is an important ingredient of S. nigrum L. and has demonstrated anticancer properties in various types of cancer. However, the effects of α‑solanine on colorectal cancer remain elusive. The aim of the present study was to assess the effects of α‑solanine on human colorectal cancer cells. The results demonstrated that α‑solanine inhibited the proliferation of RKO cells in a dose‑ and time‑dependent manner. In addition, α‑solanine arrested the cell cycle at the G0/G1 phase and suppressed the expression levels of cyclin D1 and cyclin‑dependent kinase 2 in RKO cells. α‑Solanine induced apoptosis of RKO cells, as indicated by morphological changes and positive Annexin‑FITC/propidium iodide staining. Additionally, α‑solanine activated caspase‑3, ‑8 and ‑9 in RKO cells, which contributed to α‑solanine‑induced apoptosis. α‑Solanine also increased the generation of reactive oxygen species, which contributed to caspase activation and induction of apoptosis. α‑Solanine inhibited the migration, invasion and adhesion of RKO cells, as well as the expression levels and activity of matrix metalloproteinase (MMP)‑2 and MMP‑9. In addition, α‑solanine inhibited cell proliferation, activated caspase‑3, ‑8 and ‑9, induced apoptosis, and inhibited the migration and invasion of HCT‑116 cells. Furthermore, α‑solanine inhibited tumor growth and induced apoptosis in vivo. These findings demonstrated that α‑solanine effectively suppressed the growth and metastatic potential of human colorectal cancer.

It is generally known that glioblastoma is the most common primary malignant brain tumor and that it is highly aggressive and deadly. Although surgical and pharmacological therapies have made long‑term progress, glioblastoma remains extremely lethal and has an uncommonly low survival rate. Therefore, further elucidation of the molecular mechanisms of glioblastoma initiation and its pathological processes are urgent. Arsenic resistance protein 2 (Ars2) is a highly conserved gene, and it has been found to play an important role in microRNA biosynthesis and cell proliferation in recent years. Furthermore, absence of Ars2 results in developmental death in Drosophila, zebrafish and mice. However, there are few studies on the role of Ars2 in regulating tumor development, and the mechanism of its action is mostly unknown. In the present study, we revealed that Ars2 is involved in glioblastoma proliferation and we identified a potential mechanistic role for it in cell cycle control. Our data demonstrated that Ars2 knockdown significantly repressed the proliferation and tumorigenesis abilities of glioblastoma cells in vitro and in vivo. Further investigation clarified that Ars2 deficiency inhibited the activation of the MAPK/ERK pathway, leading to cell cycle arrest in the G1 phase, resulting in suppression of cell proliferation. These findings support the conclusion that Ars2 is a key regulator of glioblastoma progression.

RAD51 is one of the pivotal enzymes for DNA double-strand break (DSB) repair by the homologous recombination (HR) pathway, which implies it as a promising and novel target for cancer therapy. Recent findings have indicated RAD51 protein is overexpressed in a variety of tumors. The high-expression of RAD51 is related to poor prognosis. RAD51 is involved in the repair of DNA damage and the generation of genetic diversity by an evolutionarily conserved mechanism. However, the exact mechanism of Rad51 in the progression of cervical cancer remains unclear. RI-1 is a small molecule that inhibits the central recombination protein RAD51. In this study, we found that RAD51 was highly expressed in invasive squamous cervical cancer (SCC). The administration of RI-1 inhibited cell growth in vitro and reduced growth of tumor xenografts in vivo with cervical cancer cells (HeLa and SiHa). Further investigation suggested that RAD51 protein significantly promoted the cell cycle transition from the G0/G1 to S phase. In addition, the inhibition of RAD51 reduced the level of the cell cycle related protein cyclin D1, but increased the levels of p21 mRNA and protein. As a DNA DSB repair enzyme, the expression of RAD51 in tumor cells possibly affects their sensitivity to anti-cancer agents. Additionally, in experiments using cisplatin and ionizing radiation, RI-1 treated cervical cancer cells, HeLa and SiHa, were sensitized to a greater extent than the untreated control. Thus, HR inhibition of RAD51 may provide yet another mechanism of therapeutic target for the chemosensitization and radiosensitization of cervical cancer with RI-1. Collectively, our data demonstrated for the first time that inhibition of RAD51 suppressed the cervical cancer cell proliferation and the growth of cervical cancer xenografts by attenuating cell cycle transition, which could be a functional link between RAD51 and cyclin D1 and p21.

Hepatoblastoma is the most common malignant liver tumor in children. Since it is often unresectable and exhibits drug resistance, the treatment of advanced hepatoblastoma is challenging. The orphan nuclear receptor liver receptor homolog‑1 (LRH‑1) serves prominent roles in malignancy; however, to the best of our knowledge, the role of LRH‑1 in hepatoblastoma remains unknown. In the present study, human hepatoblastoma cell lines were analyzed; the mRNA and protein expression levels of LRH‑1 were significantly higher in HepG2 and HuH6 cells compared with those in HepT1 cells and control THLE‑2 cells. Knockdown of LRH‑1 resulted in decreased HepG2 and HuH6 cell proliferation via downregulation of cyclin D1 (CCND1) and c‑Myc. Furthermore, treatment with an LRH‑1 antagonist (LRA) inhibited the proliferation and colony formation of cell lines in a dose‑dependent manner, and induced cell cycle arrest at G1 phase through inhibition of CCND1 expression. Finally, LRA treatment enhanced the cytotoxic effects of doxorubicin on hepatoblastoma cells. Collectively, these findings suggested that LRH‑1 may have an important role in the progression of hepatoblastoma and implicated LRA as a novel, potential therapeutic agent for the treatment of hepatoblastoma.

Keratins are fibrous structural proteins that serve essential roles in forming the stratum corneum and protect the cells in this layer of skin from damage. Keratin 17 (KRT17) is a key member of the keratins, and dysregulated expression of KRT17 has been reported in various types of cancer, such as lung and gastric cancer. The present study aimed to identify the role of KRT17 in osteosarcoma and the underlying molecular mechanism. The expression of KRT17 in osteosarcoma tissues and cell lines was detected using reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. The effects of KRT17 on osteosarcoma cell proliferation and the Warburg effect in vitro were detected using CCK‑8 and colony formation assays, cell cycle distribution analysis and metabolic measures. The effects of KRT17 on osteosarcoma cell proliferation in vivo were detected using a subcutaneous tumorigenesis model. The association between KRT17 and the AKT/mTOR/hypoxia‑inducible factor 1α (HIF1α) pathway was detected using RT‑qPCR and western blotting. The results demonstrated that KRT17 was highly expressed in osteosarcoma tissues and cell lines. Knockdown of KRT17 decreased osteosarcoma cell proliferation and colony formation, induced G1 phase arrest and inhibited glycolysis in vitro. Similarly, the suppression of KRT17 decreased osteosarcoma tumor growth in vivo. Knockdown of KRT17 decreased the expression of phosphorylated (p)‑AKT, p‑mTOR, HIF1α and the target gene of HIF1α glucose transporter 1. Restoring the expression of p‑AKT, p‑mTOR or HIF1α reversed the effect of KRT17 inhibition on cell proliferation and glycolysis. These results indicated that knockdown of KRT17 may be an effective method for treating osteosarcoma through inhibiting osteosarcoma cell proliferation and the Warburg effect by suppressing the AKT/mTOR/HIF1α pathway.

Tumor microenvironment undoubtedly has a significant impact on therapeutic responses. Abundant evidence suggests that the 3D in vitro culture holds great promise for drug discovery and development by bridging the gap between conventional 2D culture and animal models. The present study described 3D basement membrane culture of A549 cells, which mimics the complex 3D arrangement of tumors in vivo and elucidates the underlying mechanisms of microenvironmental influences on cellular functions and therapeutic efficacy. A549 cells cultured in 3D undergo G0/G1 phase arrest and decreased migratory and invasive capacity, indicating dormant cell characteristics. Hypoxia, apoptosis and stemness were demonstrated in the A549 cells in 3D architecture compared with the 2D‑cultured counterparts. More importantly, cells in the 3D environment exhibited increased resistance to different classes of anticancer agents. Western blotting revealed changes in the levels of key cancer‑associated pathways, phosphorylated (p)‑STAT3, p‑ERK, and p‑Akt, in response to 3D culture compared with 2D monolayer culture. Notably, mechanistic analysis using specific inhibitors showed that the STAT3 inhibitor overcomes the 3D culture‑induced doxorubicin and etoposide resistance. These results implicated an important role of p‑STAT3 in conferring chemoresistance in 3D‑cultured A549 cells, as well as the use of STAT3 inhibitor as a potential chemosensitizer to improve drug sensitivity. Thus, 3D culture systems, that more closely resemble in vivo tumor biology, may be more effective models in searching for novel chemotherapeutic agents and therapeutic targets for cancer treatment.