Chemoresistance In Colorectal Cancer Research Articles

The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer.

Colorectal Cancer (CRC) is one of the most common gastrointestinal malignancies which has quite a high mortality rate. Despite the advances made in CRC treatment, effective therapy is still quite challenging, particularly due to resistance arising throughout the treatment regimen. Several studies have been carried out to identify CRC chemoresistance mechanisms, with research showing different signalling pathways, certain ATP binding cassette (ABC) transporters and epithelial mesenchymal transition (EMT), among others to be responsible for the failure of CRC chemotherapies. In the last decade, it has become increasingly evident that certain non-coding RNA (ncRNA) families are involved in chemoresistance. Research investigations have demonstrated that dysregulation of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) contribute towards promoting resistance in CRC via different mechanisms. Considering the currently available data on this phenomenon, a better understanding of how these ncRNAs participate in chemoresistance can lead to suitable solutions to overcome this problem in CRC. This review will first focus on discussing the different mechanisms of CRC resistance identified so far. The focus will then shift onto the roles of miRNAs, lncRNAs and circRNAs in promoting 5-fluorouracil (5-FU), oxaliplatin (OXA), cisplatin and doxorubicin (DOX) resistance in CRC, specifically using ncRNAs which have been recently identified and validated under in vivo or in vitro conditions.

Inhibition of Heat-shock Protein 27 Reduces 5-Fluorouracil-acquired Resistance in Human Colon Cancer Cells.

In previous work we showed that expression of heat-shock protein 27 (HSP27; encoded by HSPB1) was associated with inherent resistance to 5-fluorouracil (5-FU). However, the relationship between HSP27 and acquired resistance remains unknown. We generated an acquired resistance model (WiDr-R) of a colon cancer cell line by exposing WiDr cells to 5-FU. Cell viability assays under treatment with 5-FU, as well as down-regulation of HSP27 using small interfering HSP27 RNA, were performed. HSP27 mRNA and protein expression was analyzed using real-time polymerase chain reaction and western blotting. 5-FU-acquired resistance induced overexpression of HSP27 mRNA and protein levels in WiDr-R cells. Furthermore, siRNA knockdown of HSP27 in WiDr-R cells reduced 5-FU-acquired resistance. These findings demonstrate that HSP27 is associated with 5-FU resistance in human colon cancer cell cells and suggest that HSP27 regulation represents a novel approach to overcoming chemoresistance in colorectal cancer.

TRIM Proteins in Colorectal Cancer: TRIM8 as a Promising Therapeutic Target in Chemo Resistance

Colorectal cancer (CRC) represents one of the most widespread forms of cancer in the population and, as all malignant tumors, often develops resistance to chemotherapies with consequent tumor growth and spreading leading to the patient’s premature death. For this reason, a great challenge is to identify new therapeutic targets, able to restore the drugs sensitivity of cancer cells. In this review, we discuss the role of TRIpartite Motifs (TRIM) proteins in cancers and in CRC chemoresistance, focusing on the tumor-suppressor role of TRIM8 protein in the reactivation of the CRC cells sensitivity to drugs currently used in the clinical practice. Since the restoration of TRIM8 protein levels in CRC cells recovers chemotherapy response, it may represent a new promising therapeutic target in the treatment of CRC.

ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer.

AAA domain containing 3A (ATAD3A) is a nucleus-encoded mitochondrial protein with vital function in communication between endoplasmic reticulum (ER) and mitochondria which is participated in cancer metastasis. Here we show that elevated ATAD3A expression is clinically associated with poor 5-year disease-free survival in patients with colorectal cancer (CRC), especially high-risk CRC patients who received adjuvant chemotherapy. Our results indicated ATAD3A is significantly upregulated to reduce chemotherapy-induced cancer cell death. We found that knockdown of ATAD3A leads to dysregulation in protein processing for inducing ER stress by RNA sequencing (RNA-seq). In response to chemotherapy-induced ER stress, ATAD3A interacts with elevated GRP78 protein to assist protein folding and alleviate ER stress for cancer cell survival. This reduction of ER stress leads to reduce the surface exposure of calreticulin, which is the initiator of immunogenic cell death and antitumor immunity. However, silencing of ATAD3A enhances cell death, triggers the feasibility of chemotherapy-induced ER stress for antitumor immunity, increases infiltration of T lymphocytes and delays tumor regrowth in vitro and in vivo. Clinically, CRC patients with less ATAD3A have high density of CD45+ intratumoral infiltrating lymphocytes (TILs) and memory CD45RO+ TILs. Taken together, our results suggest that pharmacologic targeting to ATAD3A might be a potential therapeutic strategy to enhance antitumor immunity for CRC patients who received adjuvant chemotherapy.

Protein\u2013protein interaction analysis reveals a novel cancer stem cell related target TMEM17 in colorectal cancer

BackgroundCancer stem cells (CSCs) are a small subpopulation of cells within tumors with stem cell property. Increased evidence suggest that CSCs could be responsible for chemoresistance and recurrence in colorectal cancer (CRC). However, a reliable therapeutic target on CSCs is still lacking.MethodsHere we describe a two-step strategy to generate CSC targets with high selectivity for colon stem cell markers, specific proteins that are interacted with CSC markers were selected and subsequently validated in a survival analysis. TMEM17 protein was found and its biological functions in CRC cells were further examined. Finally, we utilized the Gene Set Enrichment Analysis (GSEA) to investigate the potential mechanisms of TMEM17 in CRC.ResultsBy combining protein–protein interaction (PPI) database and high-throughput gene profiles, network analysis revealed a cluster of colon CSCs related genes. In the cluster, TMEM17 was identified as a novel CSCs related gene. The results of in-vitro functional study demonstrated that TMEM17 depletion can suppress the proliferation of CRC cells and sensitize CRC cells to chemotherapy drugs. Enrichment analysis revealed that the expression of TMEM17 is associated with the magnitude of activation of the Wnt/β-catenin pathway. Further validation in clinical samples demonstrated that the TMEM17 expression was much higher in tumor than normal tissue and was associated with poor survival in CRC patients.ConclusionCollectively, our finding unveils the critical role of TMEM17 in CRC and TMEM17 could be a potential effective therapeutic target for tumor recurrence and chemoresistance in the colorectal cancer (CRC).

MicroRNA-9-5p increases the sensitivity of colorectal cancer cells to 5-fluorouracil by downregulating high mobility group A2 expression.

Chemotherapy drug 5-fluorouracil (5-FU) is the first-line treatment for colorectal cancer (CRC); however, 5-FU resistance decreases CRC therapeutic efficiency. A previous study revealed that microRNA (miR)-9-5p serves an antitumor effect in CRC. However, the effect of miR-9-5p in CRC chemoresistance remains unknown. In the present study, two CRC cell lines, including HT-29 and HCT-116 cells, were used to investigate the impact of miR-9-5p in overcoming 5-FU resistance. The results revealed that treatment with 5-FU decreased CRC cell viability and upregulated miR-9-5p expression in both CRC cells. Knockdown of miR-9-5p decreased HCT-116 cell sensitivity to 5-FU and inhibited apoptosis. By contrast, miR-9-5p overexpression enhanced the sensitivity of HT-29 cells to 5-FU and induced apoptosis. Additionally, it was confirmed that miR-9-5p directly targeted high mobility group A2 (HMGA2). HMGA2 overexpression reversed miR-9-5p-induced HT-29 apoptosis. The present study indicated that miR-9-5p enhanced the sensitivity of CRC cells to 5-FU via downregulating HMGA2 expression.

Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX.

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

Inhibition of the cell migration, invasion and chemoresistance of colorectal cancer cells through targeting KLF3 by miR-365a-3p.

Background: Metastasis and chemoresistance limit treatment efficacy of colorectal cancer (CRC) patients. MicroRNAs (miRNAs) have been believed to be candidate biomarkers for tumor cell proliferation, metastasis and chemoresistance, but the related molecular mechanisms are not clear for prognosis prediction.Aims: We aimed to investigate the role of miR-365a-3p in metastasis and chemoresistance of CRC.Methods: The expression levels of miR-365a-3p in clinical CRC tissues were analyzed. The effects of miR-365a-3p expression levels on tumor chemoresistance, invasion and migration were also determined. A dual luciferase reporter gene assay was used to determine the effect of miR-365a-3p on its target gene, Kruppel-like factor 3 (KLF3), and the effect of the miR-365a-3p/KLF3 axis on CRC cell chemoresistance, migration and invasion was further investigated.Results: In patients with CRC with lymph node or distant organ metastasis or in CRC cell lines, the expression levels of miR-365a-3p were significantly downregulated. In addition, the findings of Transwell assays demonstrated that miR-365a-3p significantly suppressed CRC cell migration and invasion. The dual luciferase reporter gene assay results suggested that miR-365a-3p may play an important role in the regulation of migration, invasion and chemoresistance in CRC cells.Conclusions: The findings of present study provided evidence to suggest that miR-365a-3p may be a potential tumor suppressor gene in CRC and may inhibit the migration, invasion and chemoresistance of CRC cells. These results suggested that targeting miR-365a-3p/KLF3 axis may represent a potential therapeutic intervention for metastatic disease in patients with CRC.

Paired-like homeodomain transcription factor 2 strengthens chemoresistance in colorectal cancer by activating the Wnt/β-catenin axis.

The purpose of this study was to determine the mechanism of paired-like homeodomain transcription factor 2 (PITX2) in the chemoresistance of colorectal cancer (CRC) via the upregulation of the Wnt/β-catenin axis. CRC cells were persistently exposed to increasing 5-fluorouracil (5-FU) concentrations to establish 5-FU-resistant cells. Functional assays were conducted to examine cell viability, proliferation, and cell cycle. After the transfection of small interfering (si)-negative control and si-PITX2 in 5-FU-resistant cells, the effects of PITX2 depletion in these cells were assessed. Notably, expression of PITX2, Wnt-3a, and β-catenin, and the relation between PITX2 and Wnt-3a were verified. Additionally, an inhibitor or an activator of the Wnt/β-catenin axis was added into cells to detect the variance of the 5-FU-resistant cells. Eventually, xenograft transplantation was applied to confirm the effect of PITX2 knockdown on CRC chemoresistance to 5-FU. 5-FU-resistant CRC cells were successfully established, in which CRC cell viability, proliferation, and cell cycle were all enhanced, while PITX2 knockout led to reversed results, indicating that resistance to 5-FU in CRC was restricted. Furthermore, our findings revealed that PITX2 upregulated the Wnt/β-catenin axis. The inactivation of the Wnt/β-catenin axis resulted in the reduction of resistance to 5-FU in CRC cells; while activation of the Wnt/β-catenin axis reversed the reduced resistance to 5-FU in CRC cells caused by PITX2 knockout. Additionally, xenograft transplantation further confirmed that PITX2 knockdown reduced the resistance of HCT-116 cells to 5-FU. This study clarified that PITX2 enhanced resistance to 5-FU in CRC upregulating the Wnt/β-catenin axis.

RUNX1 regulates the proliferation and chemoresistance of colorectal cancer through the Hedgehog signaling pathway.

Background: Chemoresistance is one of the main causes of recurrence in colorectal cancer (CRC) patients and leads to a poor prognosis. To characterize RUNX1 expression in colorectal cancer (CRC) and elucidate its mechanistic involvement in the tumor biology of this disease.Methods: The expression of RUNX1 in CRC and normal tissues was detected by bioinformatics analysis. Cell proliferation was measured by CCK-8 and clonogenic assays. In vivo tumor progression was assessed with a xenograft mouse model. Cell drug sensitivity tests and flow cytometry were performed to analyze CRC cell chemoresistance. RUNX1, key molecules of the Hedgehog signaling pathway, and ABCG2 were detected by qRT-PCR and Western blotting.Results: RUNX1 expression is upregulated in CRC tissues. RUNX1 enhanced CRC cell resistance to 5-fluorouracil (5-FU), promoted proliferation, and inhibited 5-FU-induced apoptosis. Mechanistically, RUNX1 can activate the Hedgehog signaling pathway and promote the expression of ABCG2 in CRC cells.Conclusions: Our study demonstrated that RUNX1 promotes CRC proliferation and chemoresistance by activating the Hedgehog signaling pathway and ABCG2 expression.

Exosomal IDH1 increases the resistance of colorectal cancer cells to 5-Fluorouracil.

Chemoresistance challenges the clinical treatment of colorectal cancer and requires an urgent solution. Isocitrate dehydrogenase 1 (IDH1) is a key enzyme involved in glucose metabolism that mediates the malignant transformation of tumors. However, the mechanisms by which IDH1 is involved in colorectal cancer cell proliferation and drug resistance induction remain unclear. In this study, we found that IDH1 was highly expressed in human colorectal cancer tissues and could be used to indicate a high-grade tumor. In vitro gene overexpression and knockdown were used to determine whether IDH1 promoted the proliferation of the colorectal cancer cell line HCT8 and resistance to 5-Fluorouracil (5FU). Further studies have shown that the 5FU-resistant cell line, HCT8FU, secreted exosomes that contained a high level of IDH1 protein. The exosomal IDH1 derived from 5FU-resistant cells enhanced the resistance of 5FU-sensitive cells. Metabolic assays revealed that exosomes derived from 5FU-resistant cells promoted a decrease in the level of IDH1-mediated NADPH, which is associated with the development of 5FU resistance in colorectal cancer cells. Therefore, exosomal IDH1 may be the transmitter and driver of chemoresistance in colorectal cancer and a potential chemotherapy target.

FOXM1/DVL2/Snail axis drives metastasis and chemoresistance of colorectal cancer.

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Metastasis and chemoresistance are regarded as the two leading causes of treatment failure and high mortality in CRC. Forkhead Box M1 (FOXM1) has been involved in malignant behaviors of cancer. However, the role and mechanism of FOXM1 in simultaneously regulating metastasis and chemoresistance of CRC remain poorly understood. Here, we found that FOXM1 was overexpressed in oxaliplatin- and vincristine-resistant CRC cells (HCT-8/L-OHP and HCT-8/VCR) with enhanced metastatic potential, compared with HCT-8 cells. FOXM1 overexpression increased migration, invasion and drug-resistance to oxaliplatin and vincristine in HCT-8 cells, while FOXM1 knockdown using shFOXM1 impaired metastasis and drug-resistance in HCT-8/L-OHP and HCT-8/VCR cells. Moreover, FOXM1 up-regulated Snail to trigger epithelial-mesenchymal transition-like molecular changes and multidrug-resistance protein P-gp expression, while silencing Snail inhibited FOXM1-induced metastasis and drug-resistance. We further identified that disheveled-2 (DVL2) was crucial for FOXM1-induced Snail expression, metastasis and chemoresistance. Furthermore, FOXM1 bound to DVL2, and enhanced nuclear translocation of DVL2 and DVL2-mediated transcriptional activity of Wnt/β-catenin known to induce Snail expression. In conclusion, FOXM1/DVL2/Snail axis triggered aggressiveness of CRC. Blocking FOXM1/DVL2/Snail pathway simultaneously inhibited metastasis and chemoresistance in CRC cells, providing a new strategy for successful CRC treatment.

Wnt/β‑catenin signaling: Causes and treatment targets of drug resistance in colorectal cancer (Review).

Colorectal cancer (CRC) is the third most common malignant tumor in humans. Chemotherapy is used for the treatment of CRC. However, the effect of chemotherapy remains unsatisfactory due to drug resistance. Growing evidence has shown that the presence of highly metastatic tumor stem cells, regulation of non-coding RNAs and the tumor microenvironment contributes to drug resistance mechanisms in CRC. Wnt/β-catenin signaling mediates the chemoresistance of CRC in these three aspects. Therefore, the present study analyzed the abundant evidence of the contribution of Wnt/β-catenin signaling to the development of drug resistance in CRC and discussed its possible role in improving the chemosensitivity of CRC, which may provide guidelines for its clinical treatment.

Targeting REV7 effectively reverses 5-FU and oxaliplatin resistance in colorectal cancer

BackgroundDespite an enormous research effort, patients diagnosed with advanced colorectal cancer (CRC) still have low prognosis after surgical resection and chemotherapy. The major obstacle for CRC treatment is chemoresistance to front line anti-cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin. However, the mechanism of chemoresistance to these drugs remains unclear.MethodsCell viability to 5-FU and oxaliplatin was measured by the CellTiter-Glo® 2.0 Cell Viability Assay. The endogenous REV7 protein in CRC cells was detected by western blotting. The translesion synthesis (TLS) events were measured by plasmid-based TLS efficiency assay. Cell apoptosis was evaluated by caspase3/7 activity assay. The in vivo tumor progression was analyzed by HT29 xenograft mice model.ResultsIn this study, we found that expression of REV7, which is a key component of translesion synthesis (TLS) polymerase ζ (POL ζ), is significantly increased in both 5-FU and oxaliplatin resistant CRC cells. TLS efficiency analysis revealed that upregulated REV7 protein level results in enhanced TLS in response to 5-FU and oxaliplatin. Importantly, inhibition of REV7 by CRISPR/Cas9 knockout exhibited significant synergy with 5-FU and oxaliplatin in cell culture and murine xenograft model.ConclusionThese results suggest that combination of REV7 deficiency and 5-FU or oxaliplatin has strong inhibitory effects on CRC cells and identified REV7 as a promising target for chemoresistant CRC treatment.

Genomics and prognosis analysis of epithelial-mesenchymal transition in colorectal cancer patients

BackgroundThe epithelial-mesenchymal transition (EMT) plays a pivotal role in various physiological processes, such as embryonic development, tissue morphogenesis, and wound healing. EMT also plays an important role in cancer invasion, metastasis, and chemoresistance. Additionally, EMT is partially responsible for chemoresistance in colorectal cancer (CRC). The aim of this research is to develop an EMT-based prognostic signature in CRC.MethodsRNA-seq and microarray data, together with clinical information, were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. A total of 244 differentially expressed EMT-related genes (ERGs) were obtained by comparing the expression between normal and tumor tissues. An EMT-related signature of 11 genes was identified as crucially related to the overall survival (OS) of patients through univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO), and Cox regression analysis. Finally, we established a clinical nomogram to predict the survival possibility of CRC patients by integrating clinical characteristics and the EMT-related gene signature.ResultsTwo hundred and forty-four differentially expressed ERGs and their enriched pathways were confirmed. Significant enrichment analysis revealed that EMT-related signaling pathway genes were highly related to CRC. Kaplan-Meier analysis revealed that the 11-EMT signature could significantly distinguish high- and low-risk patients in both TCGA and GEO CRC cohorts. In addition, the calibration curves verified fine concordance between the nomogram prediction model and actual observation.ConclusionWe developed a novel EMT-related gene signature for the prognosis prediction of CRC patients, which could improve the individualized outcome prediction in CRC.

STK35 Is Ubiquitinated by NEDD4L and Promotes Glycolysis and Inhibits Apoptosis Through Regulating the AKT Signaling Pathway, Influencing Chemoresistance of Colorectal Cancer

The development of colorectal cancer (CRC) is often sporadic, but its etiology is multifactorial. Chemoresistance of CRC leads to tumor recurrence and poor prognosis in patients. The phosphorylation of protein kinase B (AKT) can activate metabolic reprogramming toward cellular glycolysis. Serine/threonine kinase 35 (STK35) regulates the cell cycle and is frequently associated with cancer progression, whereas little is known about its specific roles in CRC. In the current study, bioinformatics analyses were performed to investigate the relationship between STK35 and CRC prognosis. STK35 knockdown and overexpressing CRC cells were established to examine its functions in CRC. Fluorouracil (5-FU) was utilized to evaluate the effect of STK35 on CRC chemoresistance. Moreover, co-immunoprecipitation was performed to explore the ubiquitination of STK35. STK35 was highly expressed in CRC, and its protein expression was negatively correlated with the survival of CRC patients. Furthermore, STK35 overexpression could promote glycolysis, suppress apoptosis, upregulate p-AKT, and counteract the antitumor functions of 5-FU and neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) in CRC cells. NEDD4L was associated with and could ubiquitinate STK35. STK35 could be a prognostic biomarker for CRC prognosis and has promotive effects on CRC cellular activities, partially through the AKT pathway. Moreover, STK35 also interferes with the chemosensitivity of CRC.

Identification of Novel Tumor-Microenvironment-Regulating Factor That Facilitates Tumor Immune Infiltration in Colon Cancer

Colon cancer is one of the most common malignancies causing death worldwide. It is well known that the cells of the tumor microenvironment contribute to the progression and prognosis of colon cancer. However, the gene alterations and potential remodeling mechanisms in the tumor microenvironment of colon cancer remain largely unknown. In this study, immune scores from the ESTIMATE algorithm were used to discriminate between patients with high or low immune-cell infiltration. There were 42 immune differentially expressed genes (DEGs) of prognostic value identified in this study. Among them, KCNJ5 is a key factor in promoting M2 macrophage recruitment and tumor immune infiltration in colon cancer. These findings may provide novel insights for decoding the complicated interplay between cancer cells and the tumor microenvironment as well as for developing new avenues for therapeutic intervention in colon cancer.

Hedgehog-GLI signalling promotes chemoresistance through the regulation of ABC transporters in colorectal cancer cells

Colorectal cancer (CRC) is a leading cause of cancer death. Chemoresistance is a pivotal feature of cancer cells leading to treatment failure and ATP-binding cassette (ABC) transporters are responsible for the efflux of several molecules, including anticancer drugs. The Hedgehog-GLI (HH-GLI) pathway is a major signalling in CRC, however its role in chemoresistance has not been fully elucidated. Here we show that the HH-GLI pathway favours resistance to 5-fluorouracil and Oxaliplatin in CRC cells. We identified potential GLI1 binding sites in the promoter region of six ABC transporters, namely ABCA2, ABCB1, ABCB4, ABCB7, ABCC2 and ABCG1. Next, we investigated the binding of GLI1 using chromatin immunoprecipitation experiments and we demonstrate that GLI1 transcriptionally regulates the identified ABC transporters. We show that chemoresistant cells express high levels of GLI1 and of the ABC transporters and that GLI1 inhibition disrupts the transporters up-regulation. Moreover, we report that human CRC tumours express high levels of the ABCG1 transporter and that its expression correlates with worse patients’ prognosis. This study identifies a new mechanism where HH-GLI signalling regulates CRC chemoresistance features. Our results indicate that the inhibition of Gli1 regulates the ABC transporters expression and therefore should be considered as a therapeutic option in chemoresistant patients.

Long noncoding RNA ARSR is associated with a poor prognosis in patients with colorectal cancer.

As one of the leading cancer-related mortalities worldwide, colorectal cancer (CRC) shows resistance to chemotherapy mainly because of drug resistance. Existing evidence has revealed that long noncoding RNAs (lncRNAs) are related to tumorigenesis and chemoresistance scenarios. However, the mechanism by which lncRNA induces chemoresistance and the postoperative prognosis of CRC both remain unclear. The expression of a lncRNA named lncARSR in CRC tissue was tested, and its association with clinical and pathological features was analyzed. Gain-of-function and loss-of-function assays were conducted to investigate the role of lncARSR in vivo and in vitro. Functional analysis showed that overexpressing lncARSR increased oxaliplatin (OXA) resistance of CRC cells in vitro and in vivo. Moreover, lncARSR conferred chemoresistance to CRC cells. Silencing lncARSR decreased cell viability and promoted cell apoptosis after OXA treatment, whereas overexpression of lncARSR increased cell viability and reduced cell apoptosis after OXA treatment. In addition, lncARSR overexpression induced the tumor formation capacity of colorectal cancer cells. The results obtained in the present study show that up-regulation of lncARSR promoted OXA resistance in CRC. Our results also imply that lncARSR may be a candidate marker for CRC chemoresistance.

NKX6.1 Represses Tumorigenesis, Metastasis, and Chemoresistance in Colorectal Cancer.

Accumulating evidence suggests that NKX6.1 (NK homeobox 1) plays a role in various types of cancer. In our previous studies, we identified NKX6.1 hypermethylation as a promising marker and demonstrated that the NKX6.1 gene functions as a metastasis suppressor through the epigenetic regulation of the epithelial-to-mesenchymal transition (EMT) in cervical cancer. More recently, we have demonstrated that NKX6.1 methylation is related to the chemotherapy response in colorectal cancer (CRC). Nevertheless, the biological function of NKX6.1 in the tumorigenesis of CRC remains unclear. In this study, we showed that NKX6.1 suppresses tumorigenic and metastatic ability both in vitro and in vivo. NKX6.1 represses cell invasion partly through the modulation of EMT. The overexpression of NKX6.1 enhances chemosensitivity in CRC cells. To further explore how NKX6.1 exerts its tumor-suppressive function, we used RNA sequencing technology for comprehensive analysis. The results showed that differentially expressed genes (DEGs) were mainly related to cell migration, response to drug, transcription factor activity, and growth factor activity, suggesting that these DEGs are involved in the function of NKX6.1 suppressing cancer invasion and metastasis. Our results demonstrated that NKX6.1 functions as a tumor suppressor partly by repressing EMT and enhancing chemosensitivity in CRC, making it a potential therapeutic target.