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Transient receptor potential canonical (TRPC) channels are the most prominent nonselective cation channels involved in various diseases. However, the function, clinical significance, and molecular mechanism of TRPCs in colorectal cancer (CRC) progression remain unclear. In this study, we identified that TRPC1 was the major variant gene of the TRPC family in CRC patients. TRPC1 was upregulated in CRC tissues compared with adjacent normal tissues and high expression of TRPC1 was associated with more aggressive tumor progression and poor overall survival. TRPC1 knockdown inhibited cell proliferation, cell-cycle progression, invasion, and migration in vitro, as well as tumor growth in vivo; whereas TRPC1 overexpression promoted colorectal tumor growth and metastasis in vitro and in vivo. In addition, colorectal tumorigenesis was significantly attenuated in Trpc1-/- mice. Mechanistically, TRPC1 could enhance the interaction between calmodulin (CaM) and the PI3K p85 subunit by directly binding to CaM, which further activated the PI3K/AKT and its downstream signaling molecules implicated in cell cycle progression and epithelial-mesenchymal transition. Silencing of CaM attenuated the oncogenic effects of TRPC1. Taken together, these results provide evidence that TRPC1 plays a pivotal oncogenic role in colorectal tumorigenesis and tumor progression by activating CaM-mediated PI3K/AKT signaling axis. Targeting TRPC1 represents a novel and specific approach for CRC treatment.

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Neurotensin (NT) is an endogenous 13 amino acid neuropeptide with profound opioid-independent analgesic effects. This role of NT is thought to be mediated by both neurotensin receptor subtype 1 (NTS1) and neurotensin receptor subtype 2 (NTS2). NT and its receptors are widely distributed in the pain circuits in central nervous system. Thus NT might modulate pain in many structures of pain pathway, such as spinal cord, rostroventral medulla (RVM) and periaqueductal gray (PAG). Actually either intrathecal application of NT or direct injection of NT into RVM or PAG or intracerebroventricular injection of NT showed analgesic effects. NT exerted its antinociceptive effects in both acute pain and chronic pain models. The analgesic effects of NT were originally found in acute pain experiments. In the case of pathological pain, for example, formalin injection induced inflammatory pain and sciatic nerve constriction induced neuropathic pain, NT also shows antinociceptive effects. The effects exist in somatic pain as well as visceral pain induced by noxious colorectal distension (CRD) or writhing test. It should be noted that NT plays an important role in stress-induced antinociception (SIAN), especially in higher intensity stress experiments. However as a neuropeptide, NT is susceptible to degradation by peptidases and cannot cross the blood-brain barrier (BBB). Great efforts have been made to find NT analogues that are more biologically stable and could inhibit pain by systematic administration. The present review focuses on the analgesic role and the underlying mechanisms of NT and its analogues in pain, especially in chronic pain models.

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