In the histopathological diagnosis of cutaneous tumors, the differential diagnosis of squamous cell carcinoma (SCC) with crateriform architecture and keratoacanthoma (KA) is often difficult so an accurate understanding of the biological features and the identification of reliable markers of SCC and KA are crucial issues. Insulin-like growth factor 2 mRNA-binding protein-3 (IGF2BP3, also known as IMP3) is thought of as a bona fide oncofetal protein, which is overexpressed and is involved in cell proliferation, migration, and invasion in several kinds of tumors. However, the role of IMP3 in cutaneous SCC and KA has not been well studied. Therefore, we focused on studying the biological functions of IMP3 in SCC and KA. In human skin SCC cell lines, HSC-1 and HSC-5, and the human keratinocyte cell line, HaCaT, IMP3 mRNA levels were significantly higher than that of normal human skin. The knockdown of IMP3 expression reduced the proliferation of HSC-1, and significantly reduced invasion by HSC-1 and HSC-5. In contrast, the knockdown of IMP3 did not significantly affect invasion by HaCaT cells. In immunohistochemical studies of SCC and KA tissues, the Ki-67 labeling index (LI) of the suprabasal cell layer was significantly higher in SCC, compared with KA tissues and the tumor-free margin (TFM) adjacent to SCC and KA. Most SCC tissues stained strongly positive for IMP3, but KA tissues and TFM were mostly negative for IMP3. The Ki-67 LI of the IMP3-positive group was significantly higher than that of the IMP3-negative group in the suprabasal cell layer of SCC. These results suggest that IMP3 plays an important role in proliferation and, more significantly, in the invasion of SCC, and may be a suitable marker for the histopathological diagnosis of SCC with a crateriform architecture and KA. Furthermore, IMP3 may potentially be a new therapeutic target for SCC.

Interaction between tumor cells and their micro-environment has a crucial role in the development, progression and drug resistance of cancer. Our objective was to confirm the role of Hospicells, which are stromal cells from the cancer microenvironment, in drug resistance and tumor cell growth. We demonstrated that soluble factors secreted by Hospicells activate several genes and upregulate the JAK/STAT signaling pathway in ovarian cancer cell lines. Hospicells express all insulin-like growth factor (IGF) family as detected by gene array, RT-PCR, protein array and immunocytochemistry. While focusing attention on the microenvironment, we considered the role of IGF-I in proliferation and survival of ovarian cancer cells. Indeed, IGF-I is a major regulator of different stages of cancer development. We studied the effect of exogenously added IGF-I on the regulation of ATP-binding cassette (ABC) genes (MDR1, MRP1, MRP2, MRP3, MRP5 and BCRP) in the ovarian cancer cell line OVCAR3 and validated the results obtained using the IGF-IR antagonist picropodophyllin. IGF-I regulates the expression of ABC genes in OVCAR3 cells via the PI3-kinase, MEK and JAK2/STAT3 signaling pathways. The OVCAR3 cell line when co-cultured with Hospicells showed a marked degree of drug resistance. The drug resistance observed could be amplified with exogenous IGF-I. Addition of IGF-IR inhibitor, however, reduced the degree of resistance in these exposed cells. Cells that were treated with anticancer drugs and then exposed to IGF-I showed an increase in drug resistance and, thereby, an increase in cell survival. This observation indicates that drug resistance of OVCAR3 cells increases when there is synergy between OVCAR3 cells and Hospicells and it is amplified when IGF-I was exogenously added. In conclusion, inhibition of IGF-IR and targeting of the JAK2/STAT3 signaling pathway can be a target for ovarian cancer therapy.

Mounting evidence has demonstrated that microRNAs (miRNAs or miRs) play significant roles in various types of human tumors, including retinoblastoma (RB). However, the biological role and regulatory mechanisms of miRNAs in RB remain to be fully elucidated. The present study was designed to identify the regulatory effects of miRNAs in RB and the underlying mechanisms. Differentially expressed miRNAs in RB tissue were screened out based on the Gene Expression Omnibus (GEO) dataset, GSE7072, which revealed that miR‑153 in particular, displayed the highest fold change in expression. It was identified that miR‑153 was significantly downregulated in RB tissues, and its downregulation was closely associated with a larger tumor base and differentiation. Functional analysis revealed that the overexpression of miR‑153 inhibited RB cell proliferation, migration and invasion, and promoted the apoptosis of WERI‑RB‑1 and Y79 cells. In addition, insulin‑like growth factor 1 receptor (IGF1R) was identified as a target of miR‑153 in RB cells. More importantly, it was demonstrated that miR‑153 upregulation inhibited the expression of its target gene, IGF1R, which inhibited the activation of the Raf/MEK and PI3K/AKT signaling pathways. Collectively, the present study demonstrates for the first time, to the best of our knowledge, that miR‑153 functions as a tumor suppressor in RB by targeting the IGF1R/Raf/MEK and IGF1R/PI3K/AKT signaling pathways. Collectively, the findings presented herein demonstrate that miR‑153 targets IGF1R and blocks the activation of the Raf/MEK and PI3K/AKT signaling pathway, thus preventing the progression of RB. Thus, this miRNA may serve as a novel prognostic biomarker and therapeutic target for RB.

Accumulating evidence has indicated that the dysregulation of microRNAs (miRNAs) is involved in the pathogenesis o retinoblastoma (RB); however, the potential role of miR‑98 in RB remains elusive. In the present study, it was demonstrated that miR‑98 is downregulated in RB tissues and cell lines, and its expression significantly associated with clinicopathological features, including differentiation, N classification and largest tumor base; patients with low miR‑98 expression levels exhibited significantly poorer overall survival. Overexpression of miR‑98 was suggested to suppress RB cell growth, migration and invasion. In addition, insulin‑like growth factor‑1 receptor (IGF1R), a well‑reported oncogene, was identified as a potential target of miR‑98 via a luciferase assay, reverse transcription‑quantitative polymerase chain reaction and western blotting. Correlation analysis revealed a significantly negative correlation between miR‑98 and IGF1R expression in tumor tissues (n=60). In addition, the results of the present study demonstrated that IGF1R function as an oncogene by promoting RB cell viability, migration and invasion. Furthermore, restoration of IGF1R was observed to reverse the anticancer effects of miR‑98 on RB cell viability, migration and invasion. Importantly, the findings of the present study indicated that miR‑98 suppressed RB cell growth and metastasis by inhibiting the IGF1R/k‑Ras/Raf/mitogen activated protein kinase kinase/extracellular signal‑regulated kinase signaling pathway. Collectively, the present study proposed that miR‑98 may serve as a novel prognostic biomarker and therapeutic target in the treatment of RB.

Pancreatic ductal adenocarcinoma (PDAC) is a noteworthy malignant carcinoma with an unsatisfactory prognosis attributed to late diagnosis. Ubiquitin‑conjugating enzyme E2K (UBE2K) has been found to serve important roles in a number of diseases. However, its function and the exact molecular mechanism of UBE2K in PDAC remain to be elucidated. The present study discovered that UBE2K was expressed at high levels and indicated the poor prognosis of patients with PDAC. Following this, the CCK‑8, colony formation, and sphere formation assays showed that UBE2K promoted proliferation and the stemness phenotype of PDAC cells in vitro. Evidence from subcutaneous tumor‑bearing nude mice experiments further confirmed that UBE2K enhanced PDAC cell tumorigenesis in vivo. Additionally, the present study demonstrated that insulin‑like growth factor 2 RNA binding protein 3 (IGF2BP3) functioned as an RNA‑binding protein to increase UBE2K expression by enhancing the RNA stability of UBE2K. The knockdown or overexpression of IGF2BP3 could attenuate the change in cells growth induced by the overexpression or knockdown of UBE2K. In summary, the findings indicated the oncogenic roles of UBE2K in PDAC. In addition, IGF2BP3 and UBE2K constitute a functional axis to regulate the malignant progression of PDAC.

The homeobox (HOX) gene family plays a fundamental role in carcinogenesis. However, the oncogenic mechanism of HOXC10 in head and neck squamous cell carcinoma (HNSCC) remains unclear. In the present study, it was revealed that HOXC10 expression was significantly higher in HNSCC tissues than in adjacent tissues, and a high level of HOXC10 was closely associated with worse clinical outcomes. HOXC10 overexpression promoted HNSCC cell proliferation, migration, and invasion, both in vitro and in vivo. Mechanistically, chromatin immunoprecipitation sequencing revealed that HOXC10 drove the transcriptional activation of a disintegrin and metalloproteinase 17 (ADAM17), and the ADAM17/epidermal growth factor receptor (EGFR)/ERK1/2 signaling pathway facilitating the proliferation of HNSCC. Furthermore, mass spectrometric analysis indicated that HOXC10 interacted with ribosomal protein S15A (RPS15A) and enhanced RPS15A protein expression, activating the Wnt/β‑catenin pathway and contributing to invasion and metastasis of HNSCC. Additionally, the methylated RNA immune precipitation and RNA antisense purification assays showed that N6‑methyladenosine (m6A) writer, methyltransferase‑like 3, catalyzed m6A modification of the HOXC10 transcript, m6A reader insulin like growth factor 2 mRNA binding protein (IGF2BP)1 and IGF2BP3 involved in recognizing and stabilizing m6A‑tagged HOXC10 mRNA. In summary, the present study identified HOXC10 as a promising candidate oncogene in HNSCC. The m6A modification‑mediated HOXC10 promoted proliferation, migration, and invasion of HNSCC through co‑activation of ADAM17/EGFR and Wnt/β‑catenin signaling, providing a novel diagnostic and prognostic biomarker and a potential therapeutic target for HNSCC.

Cervical cancer (CC), an aggressive form of squamous cell carcinoma, is characterized by early‑stage lymph node metastasis and an extremely poor prognosis. The authors have previously demonstrated that patients with CC have aberrant glycolysis. The upregulation of receptor for activated C kinase 1 (RACK1) is associated with CC lymph node metastasis (LNM). However, its role in mediating aerobic glycolysis in CC LNM remains unclear. In the present study, 1H nuclear magnetic resonance analysis revealed a significant association between RACK1 expression and the glycolysis/gluconeogenesis pathway. Additionally, RACK1 knockdown inhibited aerobic glycolysis and lymphangiogenesis in vitro and suppressed CC LNM in vivo. Furthermore, protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling was identified as a critical RACK1‑regulated pathway that increased lymphangiogenesis in CC. Co‑immunoprecipitation, immunofluorescence and western blot analysis revealed that RACK1 activated AKT/mTOR signaling by interacting with insulin‑like growth factor 1 receptor (IGF1R). POU class 2 homeobox 2 (POU2F2) bound to the RACK1 promoter and regulated its transcription, thereby functionally contributing to glycolysis and lymphangiogenesis in CC. Of note, the administration of 2‑deoxy‑D‑glucose, which attenuates glycolysis, inhibited RACK1‑induced lymphangiogenesis in CC. The correlations between RACK1, IGF1R, POU2F2 and hexokinase 2 were further confirmed in CC tissues. Thus, RACK1 plays a crucial role in CC tumor LNM by regulating glycolysis via IGF1R/AKT/mTOR signaling. Thus, the targeting of the POU2F2/RACK1/IGF1R/AKT/mTOR signaling pathway may provide a novel treatment strategy for CC.

Osteosarcoma is the most common primary malignancy of the bone and is characterized by local invasion and distant metastasis. Over the past 20 years, long-term outcomes have reached a plateau even with aggressive therapy. Overexpression of insulin-like growth factor 1 receptor (IGF‑1R) is associated with tumor proliferation, invasion and migration in osteosarcoma. In the present study, our group developed a novel quinazoline derivative, 6-fluoro‑2-(3-fluorophenyl)-4-(cyanoanilino)quinazoline (HMJ‑30), in order to disrupt IGF‑1R signaling and tumor invasiveness in osteosarcoma U‑2 OS cells. Molecular modeling, immune-precipitation, western blotting and phosphorylated protein kinase sandwich ELISA assays were used to confirm this hypothesis. The results demonstrated that HMJ‑30 selectively targeted the ATP-binding site of IGF‑1R and inhibited its downstream phosphoinositide 3-kinase/protein kinase B, Ras/mitogen-activated protein kinase, and IκK/nuclear factor-κB signaling pathways in U‑2 OS cells. HMJ‑30 inhibited U‑2 OS cell invasion and migration and downregulated protein levels and activities of matrix metalloproteinase (MMP)‑2 and MMP-9. An increase in protein levels of tissue inhibitor of metalloproteinase (TIMP)‑1 and TIMP‑2 was also observed. Furthermore, HMJ‑30 caused U‑2 OS cells to aggregate and form tight clusters, and these cells were flattened, less elongated and displayed cobblestone-like shapes. There was an increase in epithelial markers and a decrease in mesenchymal markers, indicating that the cells underwent the reverse epithelial-mesenchymal transition (EMT) process. Overall, these results demonstrated the potential molecular mechanisms underlying the effects of HMJ‑30 on invasiveness and EMT in U‑2 OS cells, suggesting that this compound deserves further investigation as a potential anti-osteosarcoma drug.

Chordoma is a rare low‑grade tumor of the axial skeleton. Over previous decades, a range of targeted drugs have been used for treating chordoma, with more specific and effective therapies under investigation. Transmembrane Emp24 protein transport domain containing 3 (TMED3) is a novel gene reported to be a regulator of oncogenesis, cancer development and metastasis; however, its role in chordoma remains unclear. In the present study, the expression of TMED3 was investigated in chordoma cells, and the effect of TMED3 knockdown on chordoma development was examined in vitro and in vivo, followed by exploration of differentially expressed proteins in TMED3‑silenced chordoma cells via an apoptosis antibody array. Reverse transcription‑quantitative PCR and western blot assays were performed to determine the expression levels. It was revealed that TMED3 was highly expressed in chordoma, and that knockdown of TMED3 inhibited cell viability and migration, and enhanced the apoptosis of chordoma cells. Additionally, knockdown of TMED3 inhibited the expression of Bcl‑2, heat shock protein 27, insulin‑like growth factor (IGF)‑I, IGF‑II, IGF binding protein‑2, Livin, Akt, CDK6 and cyclin D1 proteins, whereas MAPK9 was upregulated. Furthermore, a xenograft nude mice model demonstrated that TMED3 expression promoted tumor growth. Collectively, the present findings suggested that knockdown of TMED3 inhibited cell viability and migration, and enhanced apoptosis in chordoma cells, and that TMED3 may be a novel target for chordoma therapy.

Hedgehog (HH) pathway Smoothened (Smo) inhibitors are active against Gorlin syndrome-associated basal cell carcinoma (BCC) and medulloblastoma where Patched (Ptch) mutations occur. We interrogated 705 epithelial cancer cell lines for growth response to the Smo inhibitor cyclopamine and for expressed HH pathway-regulated species in a linked genetic database. Ptch and Smo mutations that respectively conferred Smo inhibitor response or resistance were undetected. Previous studies revealed HH pathway activation in lung cancers. Therefore, findings were validated using lung cancer cell lines, transgenic and transplantable murine lung cancer models, and human normal-malignant lung tissue arrays in addition to testing other Smo inhibitors. Cyclopamine sensitivity most significantly correlated with high cyclin E (P=0.000009) and low insulin-like growth factor binding protein 6 (IGFBP6) (P=0.000004) levels. Gli family members were associated with response. Cyclopamine resistance occurred with high GILZ (P=0.002) expression. Newer Smo inhibitors exhibited a pattern of sensitivity similar to cyclopamine. Gain of cyclin E or loss of IGFBP6 in lung cancer cells significantly increased Smo inhibitor response. Cyclin E-driven transgenic lung cancers expressed a gene profile implicating HH pathway activation. Cyclopamine treatment significantly reduced proliferation of murine and human lung cancers. Smo inhibition reduced lung cancer formation in a syngeneic mouse model. In human normal-malignant lung tissue arrays cyclin E, IGFBP6, Gli1 and GILZ were each differentially expressed. Together, these findings indicate that Smo inhibitors should be considered in cancers beyond those with activating HH pathway mutations. This includes tumors that express genes indicating basal HH pathway activation.

Prostate cancer (PCa) is a prevalent malignancy among men, with a majority of patients presenting with distant metastases at the time of initial diagnosis. These patients are at a heightened risk of developing more aggressive castration‑resistant PCa following androgen deprivation therapy, which poses a greater challenge for treatment. Notably, the inhibition of tumor angiogenesis should not be considered an ineffective treatment strategy. The regulatory role of CDK12 in transcriptional and post‑transcriptional processes is essential for the proper functioning of various cellular processes. In the present study, the expression of CDK12 was first knocked down in cells using CRISPR or siRNA technology. Subsequently, RNA‑seq analysis, co‑immunoprecipitation, western blotting, reverse transcription‑quantitative polymerase chain reaction and the LinkedOmics database were employed to reveal that CDK12 inhibits insulin like growth factor binding protein 3 (IGFBP3). Western blot analysis also demonstrated that CDK12 promoted VEGFA expression by inhibiting IGFBP3, which involves the Akt signaling pathway. Then, CDK12 was found to promote PCa cell proliferation, cell migration and angiogenesis by inhibiting IGFBP3 through cell proliferation assays, cell migration assays and tube formation assays, respectively. Finally, animal experiments were performed for in vivo validation. It was concluded that CDK12 promoted PCa and its angiogenesis by inhibiting IGFBP3.

Hepatocellular carcinoma (HCC) is a common malignancy of the liver. HCG11 is a member of long non‑coding family, upregulation of which in HCC was proved by our previous study. In the present study, the role of HCG11 in the development of HCC was detected by focusing on the interaction between HCG11 and its target protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1). The expression status of HCG11 and IGF2BP1 was first investigated with clinical HCC samples. Then the expressions of HCG11 and IGF2BP1 were both inhibited in the human HCC cell line HepG2 and the cell viability, proliferation, apoptosis and metastasis potential of HepG2 cells were assessed. At molecular level, the expression levels of p-ERK, p-JNK, p-p38, p21 and cleaved caspase-3 were also determined to explain the pathways involved in the function of HCG11 in the progression of HCC. Expression of HCG11 and IGF2BP1 were significantly higher in HCC tissues than those in para-tumor tissues. Knockdown of both indicators led to decreased cell viability, proliferation, and migration ability in HepG2 cells while the cell apoptosis and G1 cell cycle arrest were induced after knockdown of HCG11 and IGF2BP1. In addition, suppressed activity of HCG11 and IGF2BP1 blocked the phosphorylation of anti-apoptosis factors, including ERK, JNK and p38 while the mitochondrial apoptosis in HCC cells was initiated by activation of p21 and cleaved caspase-3. HCG11 exerted its effect on HCC via interaction with IGF2BP1, leading to activation of MAPK signaling, which eventually promoted the progression of HCC.

Cluster of differentiation (CD)147, as a transmembrane glycoprotein, is highly expressed in a variety of tumors. Accumulating evidence has demonstrated that CD147 serves critical roles in tumor cell death and survival; however, the underlying mechanism requires further investigation. In the present study, it was revealed that CD147 knockdown significantly increased melanoma cell apoptosis. In addition, downregulation of CD147 reversed the malignant phenotype of melanoma, as demonstrated by the induction of tumor cell apoptosis in a xenograft mouse model. In addition, a human apoptosis antibody array was performed and 9 differentially expressed apoptosis-related proteins associated with CD147 were identified, including insulin-like growth factor-binding protein 2 (IGFBP2). Additionally, CD147 knockdown was observed to significantly decreased IGFBP2 expression at the mRNA and protein levels in melanoma cells. Providing that IGFBP2 is a downstream molecule in the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, the effects of CD147 on this particular pathway were investigated. Interestingly, the expression of phosphorylated (p)-AKT and p‑mechanistic target of rapamycin was attenuated, whereas PTEN was markedly upregulated in CD147-underexpressing melanoma cells. Furthermore, application of a PI3K‑specific inhibitor also decreased IGFBP2 expression. Importantly, IGFBP2 was highly expressed in clinical tissues of melanoma compared with the control group, and its expression exhibited a positive association with CD147. The present study revealed that CD147 served a critical role in mediating the apoptosis of melanoma cells via IGFBP2 and the PTEN/PI3K/AKT signaling pathway. IGFBP2 and CD147 were observed to be overexpressed in clinical melanoma tissues; IGFBP2 was shown to be positively associated with CD147 expression, suggesting that CD147 may be considered as a potential therapeutic target for chemotherapy or prevention for in melanoma.

VIM‑AS1, a cancer‑specific long non‑coding RNA, has been recognized as a pivotal regulator in multiple types of cancer. However, the role of VIM‑AS1 in the proliferation and resistance to anti‑androgen therapy of LNCaP and C4‑2 prostate cancer cells remains to be determined. In the current study, gain‑and‑loss experiments were used to investigate the effects of VIM‑AS on the proliferation and anti‑androgen therapy of LNCaP and C4‑2 cells. RNA sequencing, RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying mechanism of VIM‑AS1 driving prostate progression. It was demonstrated that VIM‑AS1 was upregulated in C4‑2 cells, an established castration‑resistant prostate cancer (CRPC) cell line, compared with in LNCaP cells, an established hormone‑sensitive prostate cancer cell line. The present study further demonstrated that VIM‑AS1 was positively associated with the clinical stage of prostate cancer. Functionally, overexpression of VIM‑AS1 decreased the sensitivity to enzalutamide treatment and enhanced the proliferation of LNCaP cells in vitro, whereas knockdown of VIM‑AS1 increased the sensitivity to enzalutamide treatment and reduced the proliferation of C4‑2 cells in vitro and in vivo. Mechanistically, 3‑hydroxy‑3‑methylglutaryl‑CoA synthase 1 (HMGCS1) was identified as one of the direct downstream targets of VIM‑AS1, and VIM‑AS1 promoted HMGCS1 expression by enhancing HMGCS1 mRNA stability through a VIM‑AS1/insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2)/HMGCS1 RNA‑protein complex. Rescue assays indicated that knockdown of HMGCS1 expression ameliorated the increase in proliferation and enzalutamide resistance of prostate cancer cells induced by VIM‑AS1 overexpression. Overall, the present study determined the roles and mechanism of the VIM‑AS1/IGF2BP2/HMGCS1 axis in regulating proliferation and enzalutamide sensitivity of prostate cancer cells and suggested that VIM‑AS1 may serve as a novel therapeutic target for the treatment of patients with CRPC.