Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer

Abstract

Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.

Noncoding RNAs related to the hedgehog pathway in cancer: clinical implications and future perspectives

“…Unremitting efforts have been made towards the development of small molecule inhibitors such as SMO antagonists-vismodegib [ 157 ] and cyclopamine [ 158 ], Gli antagonists-GANT61 and GANT58 [ 159 ] and additional PTCH inhibitors to block Hh signaling at various sites in recent years. Yet there have been some serious drawbacks of utilizing these Hh inhibitors for the treatment of cancer, which has been discussed in detail by Javed Z et al [ 160 ]. Hence, designing persistent small molecule inhibitors with excessive bioavailability is still a thorny question.…”

Pleiotropic effects of DCLK1 in cancer and cancer stem cells

“…Upon abnormal activation, it leads to cancer at varying organs with its active triggering ability in human CRC. With the current targeting approaches, Hh signaling targeting has been possible, but it has its side effects ( Javed et al, 2021 ). The development and application of new approaches free of side effects is the new challenge in effective human cancer eradicating techniques ( Salaritabar et al, 2019 ).…”

“…In basal cell carcinoma, mutation of the human PTCH1 gene revealed the Hh signaling pathway and its molecular association with malignancy. It was shown that a mutation in PTCH1 gene is accountable for SMO activation leading to abnormal Hh cascade activation and cancer development ( Javed et al, 2021 ). All these genes function as ligands for patched (PTCH1), a 2-pass transmembrane receptor.…”

“…The activation of the Hh pathway in adults is throughout renewal and tissue regeneration. A previous study has shown that the Hh pathway inhibits tumor progression ( Javed et al, 2021 ). Furthermore, aberrant activation of cellular signaling pathways indicates the occurrence, development, and metastasis of oral squamous cell carcinoma (OSCC) ( Patni et al, 2021 ).…”

Colonic Tuft Cells: The Less-Recognized Therapeutic Targets in Inflammatory Bowel Disease and Colorectal Cancer

“…Inhibitors of STAT3 signaling pathways (e.g., STX-0119, N4, C188-9, L61H46, or AZD9150) may help in disrupting TC-mediated effects on EMT, potentially inhibiting tumor metastasis and enhancing sensitivity to chemotherapy [ 195 , 196 ]. On the other hand, it should not be forgotten that teratogenicity, immunosuppression, autoimmune reactions, and hematological abnormalities may result from the inhibition of TGFβ or STAT3 [ 199 , 200 ]. Inhibition of TGFβ may additionally result in compromised tissue remodeling, mucosal inflammation, and impaired wound healing [ 199 ].…”