Colorectal cancer (CRC) is the third most common cancer and has a high metastasis and reoccurrence rate. Long noncoding RNAs (lncRNAs) play an important role in CRC growth and metastasis. Recent studies revealed that lncRNAs participate in CRC progression by coordinating with microRNAs (miRNAs) and protein-coding mRNAs. LncRNAs function as competitive endogenous RNAs (ceRNAs) by competitively occupying the shared binding sequences of miRNAs, thus sequestering the miRNAs and changing the expression of their downstream target genes. Such ceRNA networks formed by lncRNA/miRNA/mRNA interactions have been found in a broad spectrum of biological processes in CRC, including liver metastasis, epithelial to mesenchymal transition (EMT), inflammation formation, and chemo-/radioresistance. In this review, we summarize typical paradigms of lncRNA-associated ceRNA networks, which are involved in the underlying molecular mechanisms of CRC initiation and progression. We comprehensively discuss the competitive crosstalk among RNA transcripts and the novel targets for CRC prognosis and therapy.

https://www.mdpi.com/1422-0067/20/22/5758/pdf

Long Noncoding RNA (lncRNA)-Mediated Competing Endogenous RNA Networks Provide Novel Potential Biomarkers and Therapeutic Targets for Colorectal Cancer

Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients.

/pdf/mtorc1-as-a-regulator-of-mitochondrial-functions-and-a-33ulf1xs24.pdf

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer.

Yin Yang 1 (YY1), a dual function transcription factor, is known to regulate transcriptional activation and repression of many genes associated with multiple cellular processes including cellular differentiation, DNA repair, autophagy, cell survival vs. apoptosis, and cell division. Owing to its role in processes that upon deregulation are linked to malignant transformation, YY1 has been implicated as a major driver of many cancers. While a large body of evidence supports the role of YY1 as a tumor promoter, recent reports indicated that YY1 also functions as a tumor suppressor. The mechanism by which YY1 brings out opposing outcome in tumor growth vs. suppression is not completely clear and some of the recent reports have provided significant insight into this. Likewise, the mechanism by which YY1 functions both as a transcriptional activator and repressor is not completely clear. It is likely that the proteins with which YY1 interacts might determine its function as an activator or repressor of transcription as well as its role as a tumor suppressor or promoter. Hence, a collection of YY1-protein interactions in the context of different cancers would help us gain an insight into how YY1 promotes or suppresses cancers. This review focuses on the YY1 interacting partners and its target genes in different cancer models. Finally, we discuss the possibility of therapeutically targeting the YY1 in cancers where it functions as a tumor promoter.

The Two Sides of YY1 in Cancer: A Friend and a Foe.

Tumorigenesis is a multistep process characterized by the acquisition of genetic and epigenetic alterations. During the course of malignancy development, tumor cells acquire several features that allow them to survive and adapt to the stress-related conditions of the tumor microenvironment. These properties, which are known as hallmarks of cancer, include uncontrolled cell proliferation, metabolic reprogramming, tumor angiogenesis, metastasis, and immune system evasion. Zinc-finger protein Yin Yang 1 (YY1) regulates numerous genes involved in cell death, cell cycle, cellular metabolism, and inflammatory response. YY1 is highly expressed in many cancers, whereby it is associated with cell proliferation, survival, and metabolic reprogramming. Furthermore, recent studies also have demonstrated the important role of YY1-related non-coding RNAs in acquiring cancer-specific characteristics. Therefore, these YY1-related non-coding RNAs are also crucial for YY1-mediated tumorigenesis. Herein, we summarize recent progress with respect to YY1 and its biological implications in the context of hallmarks of cancer.

The biological implications of Yin Yang 1 in the hallmarks of cancer.

Background Long noncoding RNAs (lncRNAs) have emerged as key regulators in multiple cancers, including colorectal cancer (CRC). However, the biological functions and molecular mechanisms underlying most lncRNAs in CRC remain largely unknown. Methods A novel lncRNA (TCONS_00012883) was identified using RNA sequencing. The level of TCONS_00012883 expression in CRC was analyzed by qRT-PCR. The biological functions of TCONS_00012883 in CRC were investigated by a series of in vitro and in vivo experiments: CCK8, colony formation, EdU, flow cytometric assays, transwell assays, and mouse xenograft. The molecular mechanisms of TCONS_00012883 were demonstrated by RNA pulldown, mass spectrometry analysis, RIP, coimmunoprecipitation, RNA sequencing, chromatin immunoprecipitation, and rescue experiments. Results Elevated expression of TCONS_00012883 was confirmed in CRC and positively associated with a poor prognosis. Functionally, gain- and loss-of-function assays indicated that TCONS_00012883 promoted proliferation and metastasis of CRC cell lines in vitro and in vivo. Mechanistically, RNA pulldown and mass spectrometry analysis showed that DEAD-box helicase 3 (DDX3) was the protein partner of TCONS_00012883. Furthermore, RNA sequencing assay revealed that matrix metallopeptidase 1 (MMP1) was the downstream of TCONS_00012883. Intriguingly, we found that transcription factor (YY1) could serve as a bridge between TCONS_00012883, DDX3, and MMP1. Conclusions TCONS_00012883 significantly promoted CRC progression via the DDX3/YY1/MMP1 axis, and thus, may act as a major role in diagnosis and therapy of CRC.

TCONS_00012883 promotes proliferation and metastasis via DDX3/YY1/MMP1/PI3K-AKT axis in colorectal cancer.

Introduction: It has been reported that long noncoding RNAs (lncRNAs) are crucial regulators in progression of human cancers, including colorectal cancer (CRC). However, the function of lncRNA ARAP1 antisense RNA 1 (ARAP1-AS1) in CRC remains unclear. Aim: The aim of this study was to investigate the function and molecular mechanism of lncRNA ARAP1-AS1 in CRC. Results: ARAP1-AS1 was highly expressed in CRC tissues and cell lines. ARAP1-AS1 knockdown suppressed cell migration, invasion, and epithelial-mesenchymal transition (EMT). YY1 transcription factor (YY1) enhanced the transcription activity of ARAP1-AS1. The YY1/ARAP1-AS1 axis promoted CRC cell migration and invasion. YY1/ARAP1-AS1 could regulate the Wnt/β-catenin signaling pathway. Conclusions: This study revealed that YY1-induced upregulation of ARAP1-AS1 promoted cell migration, invasion, and EMT process in CRC through the Wnt/β-catenin signaling pathway.

YY1-Induced Upregulation of Long Noncoding RNA ARAP1-AS1 Promotes Cell Migration and Invasion in Colorectal Cancer Through the Wnt/β-Catenin Signaling Pathway.

Immune checkpoint inhibitors (ICIs) have become important treatment strategies, yet responses vary among patients and predictive biomarkers are urgently needed. Mutations in KMT2C and KMT2D lead to increased levels of genomic instability. Therefore, we aimed to examine whether KMT2C/D mutations might be a predictor of immunotherapeutic efficacy. Here, we investigated the associations of KMT2C/D loss‐of‐function (LOF) variants with tumor mutation burden (TMB), MSI‐H, PD‐L1 expression, the levels of tumor‐infiltrating leukocytes (TILs), and clinical response to ICIs. It was found that KMT2C/D LOF variants were associated with higher TMB. Compared with the non‐LOF group, the proportion of patients with MSI‐H tumors was larger in the LOF group. PD‐L1 expression was higher in the LOF group only for colorectal cancer in both the Chinese and The Cancer Genome Atlas cohorts. Importantly, KMT2C/D LOF variants were associated with decreased regulatory T cells and increased levels of CD8+ T cells, activated NK cells, M1 macrophages, and M2 macrophages in colorectal cancer. However, there was no significant association between KMT2C/D LOF and TILs levels in other cancer types. Consistently, the results showed that KMT2C/D LOF variants were associated with prolonged overall survival only in colorectal cancer (p = 0.0485). We also presented that patients with KMT2C/D LOF mutations exhibited a better clinical response to anti‐PD‐1 therapy in a Chinese colorectal cancer cohort (p = 0.002). Taken together, these results suggested that KMT2C/D LOF variants could be a useful predictor for ICIs efficacy in colorectal cancer. In addition, the predictive value of KMT2C/D LOF variants was consistent with their association with TILs levels.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cas.15716

Association of KMT2C/D loss‐of‐function variants with response to immune checkpoint blockades in colorectal cancer

The long noncoding RNA MNX1-AS1 has been reported to facilitate the progression of glioblastoma and ovarian cancer. Nevertheless, the biological roles and underlying mechanisms of MNX1-AS1 in colon adenocarcinoma have not been studied until now. In the current study, MNX1-AS1 was upregulated in colon adenocarcinoma. JASPAR prediction tool showed that E2F1 could bind to the promoter region of MNX1-AS1. The chromatin immunoprecipitation assay and luciferase reporter assay were used to verify the interactions between MNX1-AS1 and E2F1. Then functional assays revealed that downregulation of MNX1-AS1 decreased cell proliferation, migration, and invasion in colon adenocarcinoma, but upregulation of E2F1 reversed the effects. Moreover, subcellular fractionation assay manifested that MNX1-AS1 was enriched in the cytoplasm of colon adenocarcinoma cells, thus we speculated whether MNX1-AS1 could function as a competing endogenous RNA (ceRNA) to play roles in colon adenocarcinoma. Bioinformatics analysis and luciferase reporter assay indicated that MNX1-AS1 could sponge microRNA-218-5p (miR-218-5p). Furthermore, we discovered that SEC61A1 was downstream target of miR-218-5p, and MNX1-AS1 acted as a ceRNA to upregulate the expression of SEC61A1 through sponging miR-218-5p. Finally, rescue assays confirmed that MNX1-AS1 facilitated the progression of colon adenocarcinoma through regulating miR-218-5p/SEC61A1 axis. Taken together, we concluded that E2F1-mediated MNX1-AS1-miR-218-5p-SEC61A1 feedback loop contributed to the progression of colon adenocarcinoma.

E2F1-mediated MNX1-AS1-miR-218-5p-SEC61A1 feedback loop contributes to the progression of colon adenocarcinoma.

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YY1-Induced Upregulation of Long Noncoding RNA ARAP1-AS1 Promotes Cell Migration and Invasion in Colorectal Cancer Through the Wnt/β-Catenin Signaling Pathway.

Association of KMT2C/D loss‐of‐function variants with response to immune checkpoint blockades in colorectal cancer

E2F1-mediated MNX1-AS1-miR-218-5p-SEC61A1 feedback loop contributes to the progression of colon adenocarcinoma.